Intraocular devices, systems, and methods

ABSTRACT

The present disclosure relates to intraocular implants for treating a condition of the eye, wherein the implant is configured to deliver a drug to the eye. The present disclosure also relates to methods of treating a condition of the eye by delivering a drug from intraocular implants to the posterior chamber (e.g., sulcus), iridocorneal angle, sclera, cornea, limbus, and vitreous.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.63/194,824 filed May 28, 2021, the disclosure of which is herebyincorporated by reference in its entirety.

TECHNICAL FIELD

This invention relates generally to intraocular implants (e.g.,drug-eluting implants) for treating conditions of the eye, andassociated methods and systems for treating such conditions of the eye.

BACKGROUND

Glaucoma is a group of optic neuropathies associated with specificstructural changes to the optic nerve ultimately leading to irreversiblevisual field loss. In many cases, this loss of vision is progressive andleads to blindness if untreated. According to the National Eye Instituteat the United States National Institutes of Health, glaucoma is theleading cause of irreversible blindness worldwide. In 2020,approximately three million people in the United States carry adiagnosis of glaucoma. Worldwide, that number is 80 million people. By2040, it is expected that over 110 million people will be living withthis potentially blinding condition (“Global Prevalence of Glaucoma andProjections of Glaucoma Burden through 2040”, Ophthalmology 2014;121:2081-2090). Glaucoma generally falls into two categories: open angleglaucoma and closed angle glaucoma. Open angle glaucoma is approximatelyseven times more common than the closed angle form in both the U.S. andEurope (Quigley H A, Broman A T. Br. J. Ophthalmol. 2006;90(3):262-267). The course of both forms of the disease is, typically, achronic and progressive loss of vision, leading to constriction of thevisual field. The ultimate result is permanent blindness. Because it istypically asymptomatic until the disease is significantly advanced,early diagnosis through regular eye exams and early treatment arecritical. While the prevalence of glaucoma increases with age, themajority of patients with undiagnosed glaucoma are under 60 years of age(Shaikh Y, Yu F, Coleman A L. Am. J. Ophthalmol. 2014;158(6):1121-1129).

Risk factors associated with glaucoma include family history, ethnicorigin, and age. Having a first degree relative with glaucoma isassociated with a significantly increased risk (Wolfs R C, Klaver C C,Ramrattan R S, van Duijn C M, Hofman A, de Jong P T. Arch Ophthalmol.1998; 116(12):1640-1645). Black and Hispanic individuals have increasedprevalence of open angle glaucoma. Additionally, they are oftendiagnosed with more severe disease. Asian, Southeast Asian, AsianIndian, and Inuit individuals are more often diagnosed with closed angleglaucoma (see e.g., Varma R, Ying-Lai M, Francis B A, et al.; LosAngeles Latino Eye Study Group. Ophthalmology 2004; 111(8):1439-1448;Tielsch J M, Sommer A, Katz J, Royall R M, Quigley H A, Javitt J. JAMA.1991; 266(3):369-374; Wormald R P, Basauri E, Wright L A, Evans J R. Eye(Loud). 1994; 8(Pt 3):315-320; and Arkell S M, Lightman D A, Sommer A,Taylor H R, Korshin O M, Tielsch J M. Arch. Ophthalmol. 1987;105(4):482-485).

Closed angle glaucoma typically results from anatomic obstruction of theanterior chamber angle and its associated drainage channels. Theanatomic obstruction prevents aqueous humor from efficiently reachingthe drainage channels thereby resulting in increased intraocularpressure. Surgical iridectomy, laser iridotomy, or lensectomy are oftenconsidered more definitive surgical options versus more palliativemedical therapy such as cholinergic drugs (e.g., pilocarpine eyedrops)to relive obstruction by pupil constriction.

Open angle glaucoma (OAG) is much more common in the U.S., and itaccounts for significantly more loss of vision that its closedcounterpart. While the exact pathophysiology of OAG is not completelyunderstood, it has been demonstrated that increased intraocular pressure(IOP) correlates with retinal ganglion cell death. There is arelationship between secretion of aqueous humor by the ciliary body andits egress from the eye via conventional trabecular meshwork pathwaysand the unconventional uveoscleral pathway. This relationship and anyresultant imbalances determine IOP. It is felt that an increasedresistance to outflow in the trabecular meshwork or more distal aqueouscollector channels are associated with increased IOP in OAG. IncreasedIOP may cause mechanical stress on the lamina cribrosa, where retinalganglion cell axons exit the eye to coalesce into the optic nerve.IOP-induced stress at the lamina cribrosa can deform, damage, andinterfere with the retinal axons leading to irreversible injury andvision loss. While such IOP associated damage typically occurs when thepressure is above the population average pressures, it can occur atlower or “normal” pressure depending on an individual's vulnerability.Conversely, many people with higher-than-average IOP never developglaucoma. A growing number of studies are identifying genomic lociassociated with glaucoma susceptibility. Thus, glaucoma may develop inpatients with an intraocular pressure relatively high for theirindividual susceptibility (see e.g., Thorleifsson G, Walters G B, HewittA W, et al. Nat Genet. 2010; 42(10):906-909; and Wiggs J L, Yaspan B L,Hauser M A, et al. PLoS Genet. 2012; 8(4):e1002654). When ganglion celldeath does occur in glaucoma, characteristic changes in the optic nervehead and the nerve fiber layer become evident. This eventually isassociated with characteristic visual field loss patterns. Promptreferral to an eye care specialist is critical to treat the glaucoma andslow the progression of irreversible damage and subsequent loss ofvision. There is no single gold standard test for diagnosing glaucoma.Typically, several criteria are taken into consideration in making thediagnosis of glaucoma. These include age, family history, ethnicbackground, IOP, corneal thickness, optical coherence tomographicanalysis of various retinal tissues, optic nerve head appearance, andperipheral visual field testing.

The primary goal of treatment is to slow progressive optic nerve damagein order to preserve vision and quality of life. Early diagnosis andintervention are critical given that visual loss is irreversible.Reduction of IOP with treatment combined with continuous diagnosticassessments of treatment efficacy are part of the mainstay of glaucomacare.

Initially, treatment is typically comprised of the least number ofmedications required to adequately reduce IOP. Medications include drugsfrom the following families of compounds: prostaglandins,beta-adrenergic blockers, alpha-adrenergic agonists, carbonic anhydraseinhibitors, Rho-kinase (ROCK) inhibitors, and cholinergic drugs.

Should medical therapy fail, not be tolerated, or not be possible, otherforms of therapy may be added or substitute to medical therapy. Forexample, laser therapy to the eye in the form of trabeculoplasty,cycloablation (endoscopic or transscleral) may be performed. In moreadvanced cases or under some circumstances, incisional surgery can beconsidered. Trabeculectomy, valves, or shunts can be used to helpcontrol IOP. Recently, minimally invasive glaucoma surgery or MIGS hasbecome a popular surgical approach to the treatment of glaucoma. Varioustechnologies are being employed to reduce IOP while reducing exposure tosurgical risks posed by more invasive treatments like trabeculectomy orvalve placement. In 2017, nearly 175,000 surgical procedures wereperformed. The surgeries included over 20,000 trabeculectomies, 20,000glaucoma drainage implants, and over 130,000 MIGS procedures (Ma A K,Lee J H, Warren J L, Teng C C. Clin Ophthalmol. 2020; 14:2551-2560).

While medical therapy is the preferred initial treatment of OAG in theU.S., it does have many problems. Drops can be cost prohibitive forpatients, and patients can forget to regularly use them. Additionally,proper instillation into the conjunctival cul-de-sac may be moredifficult, especially in the hands of the elderly or arthritic.Excessive instillation, such as instilling multiple drops, andsubsequent wasting of medication is also an issue. However, even withproper instillation of the eyedrops, medication is wasted. For instance,a typical eyedrop may be 60-90 microliters, but the ocular surface cantypically hold no more than 10 microliters. The therapeutic ingredientsand the preservatives with which they are often combined can lead toocular surface disease, discomfort, inflammation, dry eye, and reducedcorneal sensitivity, all of which can irritate the eye and furtherreduce compliance. Multiple eyedrop medications can also lead toconfusion and misuse of the medications. All of these factors combine tocreate problems with the mainstay of glaucoma therapy-drugs. However,medications do avoid a lot of the more serious complications that canoccur with surgery.

Surgical therapy of glaucoma is typically reserved as a second linetherapy in the U.S. That is gradually changing with microinvasiveglaucoma surgery (MIGS) becoming more mainstream. Nonetheless, glaucomasurgery carries its own risks. One of the more problematic complicationsis bacterial endophthalmitis, which is a potentially visuallydevastating ocular infection. However, there are many othercomplications of glaucoma surgery, including failure, hypotony,hemorrhage, malignant glaucoma, progression, hyphema, retinaldetachment, and many others. Moreover, there are long term complicationswith trabeculectomy plus antimetabolite and glaucoma drainage devices.

While glaucoma has been covered in more detail here, many other oculardiseases are being successfully treated with drugs. In addition to beingused to medically treat various ocular diseases, drugs are also oftenused as an adjunct in the surgical treatment of ocular diseases. Theyare used to treat ocular surface disease, corneal disease, scleraldisease, uveal disease, vitreous disease, and chorioretinal disease.

Age-related macular degeneration (AMD) is a common cause of vision lossin the U.S., and it is globally the third leading cause of blindness. Itis associated with degeneration of the retinal pigment epithelium andBruch's membrane. This itself can lead to overlying retinal damage andvisual loss. Unlike the aforementioned “dry” degeneration, furtherdegeneration and resulting in growth of neovascularization from theunderlying choriocapillaris can lead to significant visual loss. Thislatter process is called “wet” macular degeneration. One of the morecommon forms of treatment is regular intravitreal injections ofantibodies or drugs targeting vascular endothelial-derived growth factor(VEGF). Patients often need to receive such injections with anti-VEGFdrugs, typically antibody-derived therapeutics, including ranibizumab,aflibercept, or bevacizumab every 4-8 weeks to control their wet maculardegeneration. There are significant issues with cost, complications, andassociated morbidity with this mainstay of treatment.

Other retinal diseases require drug treatment, including macular edema,vascular occlusions, diabetic retinopathy, retinal degenerations, andretinal dystrophies. Uveal diseases can affect the choroid, ciliarybody, and iris. Examples include iritis and other forms of uveitis whichcan respond well to various drugs such as steroids. Steroids are oftengiven as oral treatments or as topical therapy. More aggressivecytotoxic agents and chemotherapy can be employed for more severe caseslike Behcet's disease.

The vitreous can also be a location for ocular disease. It may harborvision obstructing opacities or hemorrhage. In other instances, it mayaccumulate inflammatory cells in the setting of vitritis which can alsolead to visual loss.

The lens in the eye is subject to a number of diseases. The most commonare age related. Lens opacity or cataract often requires surgicalcorrection in the form of cataract surgery. While many drugs have beenused to slow cataract formation, none have so far proven to besignificantly effective. After cataract surgery, a variety of drugs areoften used to reduce likelihood of infection or inflammation.

The cornea can become opaque, scarred, or deformed because of diseasessuch as herpes zoster or simplex infection, keratitis, keratoconus, orother corneal degenerations. Additionally, transplanted corneas cansuffer from immune mediated rejection.

Scleral disease can result from immune processes or infections. In fact,one of the most common ocular diseases is myopia or nearsightedness, andit is believed that the sclera plays a critical role in axial length andrefractive state of the eye. Dilute topical atropine which may work byinducing cycloplegia, or paralysis of the ciliary body, has been shownto reduce development of axial myopia in children. Complex pathwayslikely account for the development of myopia in children. There is greatinterest in this area given the large percentage of the world'spopulation that is affected.

Drugs can be administered for these, and other, ocular diseases invarious ways. While there are systemic routes of administration such asoral or intravenous drug administration, the eye is particularly wellsuited to local administration because of its location on the surface ofthe body. Thus, local routes of drug administration are preferred in themajority of cases. This allows limited exposure of the rest of the bodyto drug and reduces the amount of drug needed. Currently, the mostcommon route of drug administration for glaucoma is a topical eyedropapproach. Such topically administered drugs typically diffuse across thecornea and into the eye. For retinal diseases, drug injection is acommon route.

Given the above-described difficulty in treating diseases such as, forexample, glaucoma and age-related macular degeneration, there is a needfor safer, more effective, and convenient treatments which address theshortcomings of the current standards of care.

SUMMARY

Intraocular implants for treating a condition of the eye and methods oftheir use are disclosed herein. In some variations, the intraocularimplant comprises: an elongate implant body comprising a first end and asecond end, wherein the elongate implant body is configured to bepositioned at least partially in the sclera such that the first end ofthe elongate implant body is positioned in the sulcus or anteriorchamber; at least one anchoring element coupled to or formed from theelongate implant body; and a drug, wherein the implant is configured todeliver the drug to the eye.

In some variations, the intraocular implant for treating a condition ofthe eye comprises an elongate implant body configured to be positionedintramurally in one or more of the sclera, the cornea, and the limbus;and a drug-eluting matrix configured to release a drug to the eye,wherein the drug-eluting matrix coats an exterior surface of theelongate implant body or is contained within an interior chamber of theelongate implant body.

In some variations, an intraocular implant comprises a spherical orrod-shaped implant body configured to be positioned entirely in thesclera; wherein the spherical or rod-shaped implant body comprises anerodible drug-eluting matrix.

In some variations, an intraocular implant comprises an implant bodyconfigured to be positioned partially or entirely in the limbus. Theimplant body may comprise an erodible drug-eluting matrix.

Also disclosed herein are methods of treating a condition in the eye ofa subject. In some variations, the method comprises advancing adrug-eluting implant through the conjunctiva and the sclera of the eyeof the subject; positioning a portion of the drug-eluting implant in thesclera and a first end of the implant in the sulcus; and delivering adrug from the drug-eluting implant to the sulcus of the subject toreduce a symptom of the condition of the eye.

Methods of treating a condition of the eye of a subject may also involveadvancing a drug-eluting implant through the sclera of the eye andpositioning the implant fully intramurally, with at least a portion inthe limbus. In this way, a drug may be delivered to a tissue orstructure of the eye, such as the anterior chamber, to reduce a symptomof the condition of the eye.

Also disclosed herein are methods of place a drug-eluting implant atleast partially within the limbus of an eye of a subject. This placementmay involve advancing the distal tip of a cannula containing the implantinto an anterior chamber of the eye and retracting the cannula torelease the implant at least partially within the limbus.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a cross-sectional view of the anatomy of a normal humaneye.

FIGS. 2A-2J shows a variety of exemplary intraocular implants.

FIGS. 3A-3C show exemplary intraocular implants comprising differentanchoring elements. FIG. 3D shows an exemplary intraocular implantcomprising a lumen and a drug reservoir.

FIGS. 4A-4E show exemplary variations of housings of intraocularimplants comprising a drug.

FIGS. 5A-5E show exemplary reservoirs for use in intraocular implants.

FIG. 6 shows an exemplary intraocular implant with a first endpositioned in the ciliary sulcus, an extension of the posterior chamber,and a second end positioned in the subconjunctival space.

FIG. 7 shows an exemplary intraocular implant with a drug-elutingreservoir or housing positioned in the sulcus and a second endpositioned in the subconjunctival space.

FIG. 8 shows another exemplary intraocular implant with a first endpositioned in the sulcus and a second end positioned in thesubconjunctival space.

FIG. 9 shows an exemplary intraocular implant with a first endpositioned in the sulcus and a second end positioned entirely in thesclera.

FIG. 10 shows an exemplary intraocular implant positioned entirely inthe sclera and an exemplary intraocular device positioned entirely inthe cornea, limbus, and sclera.

FIG. 11 shows an exemplary intraocular implant positioned entirely inthe limbus and cornea and an exemplary intraocular implant positionedentirely in the limbus and sclera

FIG. 12 is a cross-sectional view of an exemplary delivery device usedto deliver an intraocular implant into the eye of a subject.

FIG. 13 shows an exemplary intraocular device delivery device.

FIG. 14 shows another variation of an exemplary delivery device suitablefor implanting intraocular devices.

FIG. 15 shows an exemplary intraocular implant partially delivered tothe eye.

FIG. 16 shows an exemplary implant body traversing the cornea with adrug-eluting reservoir or housing positioned within the anteriorchamber.

FIG. 17 shows an exemplary intraocular device with an implant bodytraversing the sclera and a drug-eluting reservoir or housing positionedwithin the vitreous.

FIG. 18 shows an exemplary spherical intraocular device with an implantbody traversing the sclera, where the first end of the implant bodyresides in Berger's Space.

FIG. 19 shows an exemplary spherical intraocular device with an implantbody traversing the sclera, where the first end of the implant bodyresides in the Petit's Canal.

FIG. 20 shows a spherical implant body residing fully within the sclera.

FIG. 21 shows an exemplary intraocular implant residing fully within thesuprachoroidal space.

FIG. 22 shows an exemplary intraocular implant residing partially withinthe suprachoroidal space, where the first end resides in the anteriorchamber.

FIGS. 23A-23G depict a variation of a method for placing a drug-elutingimplant at least partially within the limbus of an eye. FIG. 23A showsan exemplary pre-procedure setup, FIG. 23B shows an exemplary approachof a cannula of a delivery device toward the sclera, FIGS. 24C and 24Dshow advancement of the distal tip of the cannula into and through thesclera and limbus, respectively, FIG. 24E shows advancement of thedistal tip of the cannula into the anterior chamber, FIG. 24F showsretraction of the cannula to release the drug-eluting implantintramurally, and FIG. 24G shows an exemplary final position of thedrug-eluting implant.

FIG. 24A and FIG. 24B show the concentrations of bimatoprost and thebimatoprost acid metabolite, respectively, for three pigs (A1, A2, andA6) implanted with the intrascleral implant in an animal study. FIG. 24Cand FIG. 24D show the concentrations of bimatoprost and the bimatoprostacid metabolite, respectively, for three pigs (A3, A4, and A5) implantedwith the limbal implant in an animal study.

DETAILED DESCRIPTION

Described herein are devices, systems, and methods for treatingconditions of the eye (e.g., glaucoma, macular degeneration, and othersas described herein). Generally, such devices are intended to beimplanted in the eye (e.g., within one or more of the sclera, cornea,limbus, and ciliary sulcus) to release one or more drugs to one or moreregions impacted by a disease or condition of the eye. For instance, thedevices described herein may be drug-eluting implants. In someinstances, the devices may be positioned with at least one end extendinginto the posterior chamber (e.g., within the sulcus, within the sulcusand partially extending into the remainder of the posterior chamber).For example, in some variations, the devices may be positioned withinthe sclera or partially within the sclera and the subconjunctival space,with one end extending into the sulcus. In other variations, the devicesmay be positioned intramurally within the eye. As used herein,intraocular implants (e.g., a drug-eluting implant) may be positionedintramurally when they are embedded fully within one or more tissues ofthe eye (e.g., sclera, limbus, cornea). In some variations, theintraocular implants may be positioned fully intramurally such that theyare fully within the sclera, fully within the limbus, partially in thelimbus and partially in the sclera, or partially in the limbus andpartially in the cornea.

The devices described herein may generally comprise intraocular implants(e.g., a drug eluting implant) for treating one or more conditions ofthe eye. The intraocular implants may comprise implant bodies, such as,for example, elongate implant bodies, that may deliver one or more drugsto the eye, and/or that may be coupled to a housing or reservoir thatmay contain and deliver one or more drugs to the eye. For example, insome variations, the implants may comprise a drug-eluting matrixconfigured to release one or more drugs into the eye. The intraocularimplants may further comprise at least one anchoring element, which maybe coupled to the implant body and/or may be formed from the implantbody itself. The anchoring element may be configured to secure theintraocular implant in the desired position within the eye. In somevariations, and as will be discussed in more detail herein, the implantbody may comprise a filament, a rectangular prism, a sheet, a sphere, aspheroid, an ovoid, a cylinder (e.g., a cylindrical capsule, acylindrical rod), a coil, a screw, and/or a tubular body. In somevariations, an implant body may have one or more sharpened, pointed,and/or triangular-shaped ends. An implant body may be configured as aneedle, for instance a microneedle. Systems described herein maygenerally comprise one or more intraocular implants and one or moredelivery devices configured to deliver the intraocular implants to aneye of a subject. Moreover, in some instances, one or more intralocularimplants (e.g., two, three, four, or more) and one or more deliverydevices (e.g., two, three, four, or more) may be packaged as a kit, andthe kit may contain the same number of intraocular implants as deliverydevices, or a different number of intraocular implants and deliverydevices. In some instances, an intraocular implant may be preloaded in acorresponding delivery device, while in other variations, one or moreimplants may be provided separately from a delivery device, and theimplant may be loaded into or otherwise positioned within a deliverydevice (e.g., within a cannula of a delivery device) by a user. In somevariations, multiple implants may be delivered sequentially. In somevariations, one or more implants may be delivered simultaneously. Forinstance, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more implants may be deliveredsequentially or simultaneously.

Methods for treating conditions of the eye may generally compriseadvancing a drug-eluting implant into the eye, positioning at least aportion of the drug-eluting implant in a location in the eye, anddelivering the one or more drugs from the implant to the implantlocation or another location in the eye to treat the condition of theeye and/or reduce one or more symptoms associated with the condition ofthe eye. For example, in some variations, methods may generally compriseadvancing a drug-eluting implant through the conjunctiva and the scleraof the eye, positioning a portion of the implant in the sclera and afirst end of the implant in the sulcus, and delivering a drug from theimplant to the sulcus to treat the condition of the eye and/or to reduceone or more symptoms of the condition of the eye. In some variations,methods may generally comprise advancing a drug-eluting implant throughthe conjunctiva and the cornea of the eye, positioning a portion of theimplant in the cornea and a first end of the implant in the anteriorchamber, and delivering a drug from the implant to the anterior chamberto treat the condition of the eye and/or to reduce one or more symptomsof the condition of the eye. The implant may partially reside in theiridocorneal angle of the anterior chamber. In some variations, thefirst end of the implant may reside in the iridocorneal angle of theanterior chamber. In other variations, methods may generally includeadvancing a drug-eluting implant through one or more of the sclera,limbus and cornea of the eye, positioning the implant entirely withinone or more of the sclera, limbus, cornea, and suprachoroidal space, anddelivering a drug from the implant to the anterior chamber of the eye totreat the condition of the eye and/or reduce one or more symptomsassociated with the condition of the eye. In other variations, methodsmay generally include advancing a drug-eluting implant through thesclera and limbus of the eye, positioning the implant with one end ofthe implant in the sclera and one end in the limbus, and delivering adrug from the implant, via diffusion through the limbal tissue, to theanterior chamber of the eye to treat the condition of the eye and/orreduce one or more symptoms associated with the condition of the eye. Insome variations, the drug-eluting implant may comprise one or moresharp, pointed, and/or triangular-shaped ends. For example, in somevariations, the drug-eluting implant may be in the form of a needle ormicroneedle. In some instances, the pointed, sharpened and/ortriangular-shaped end(s) may assist in placing the implant within theeye such that the implant may at least partially serve as its owndelivery system (e.g., the implant may advance through one or moretissues of the eye by means of its one or more sharp, pointed, and/ortriangular-shaped ends). Additionally or alternatively, such implantsmay be advanced using a delivery device. Conditions of the eye mayinclude, but are not limited to, ocular surface diseases, cornealdiseases, scleral diseases, uveal diseases, vitreous diseases, opticnerve diseases, choroidal diseases, and retinal diseases.

Generally, implantation of the intraocular implants described herein maybe performed in a doctor's office by general ophthalmologists and thusdo not require costly surgery performed by a specialist. Moreover,because the implants are at least partially embedded (e.g., at leastpartially embedded in the sclera, fully embedded in the sclera, cornea,limbus, or a combination thereof) in portions of the eye other than theanterior chamber, use of the implants described may greatly minimize therisk of endothelial cell loss that can occur as a result of freemovement of devices (e.g., implants or portions thereof) in the anteriorchamber. Some implants are fully embedded in a tissue of the eye and donot extend into the anterior or posterior chambers. The sclera is atough, dense, collagenous wall this is considered relatively impermeableto various chemicals, however intramural (e.g., fully intramural,partially intramural) implants described herein may provide targetedrelease of drugs through various tissues of the eye to the desiredlocation, including through the sclera.

Additionally, implants that partially or completely reside in theposterior chamber (e.g., within the sulcus, within the sulcus andpartially extending into the remainder of the posterior chamber) mayutilize naturally occurring currents (e.g., anterior flowing currents,posteriorly flowing currents), that may deliver a drug to differentportions of the eye. For example, it has been shown that aqueous humorproduced at the ciliary body and released into the ciliary sulcus and/orposterior chamber can travel anteriorly into the anterior chamber whereit travels via convection currents. Thus, in some variations, theimplants described herein may be positioned outside of the anteriorchamber, thus avoiding the risks associated with conventional implantspositioned at least partially within the anterior chamber, and maydeliver one or more drugs to the front of the eye (e.g., the anteriorchamber). Additionally, newer evidence shows that there is likely aposterior current to aqueous flow into the vitreous and across theretina and retinal pigment epithelium. Although this accounts for aminority of aqueous flow relative to anterior flowing currents, drugsreleased into the ciliary sulcus from the devices described herein maybe able to reach other target anatomy via posterior flows.

Accordingly, the devices, systems, and methods described herein mayprovide effective treatment for many conditions of the eye whileavoiding the costs and consequences of utilizing formal operating rooms,decreasing the total amount of drug needed, reducing or eliminatingsystemic drug exposure through spatially targeted delivery, decreasingor eliminating the need for frequent injections or daily eyedrops, andincreasing patient compliance with suggested treatment regimens byeliminating repeated administration of eye drops or injections used inconventional treatments. The devices, systems, and methods describedherein may deliver a much smaller amount of drug to target tissuewithout compromising on efficacy, and thus drug and preservative sideeffects may be reduced.

Anatomy

For context, FIG. 1 shows a partial cross-sectional view of the anatomyof a normal human eye. The eye can be conceptualized as a fluid filledsphere. Anteriorly, it is bounded by the cornea (100), a three-layeredclear tissue that allows entry of light, and functions like a protectivewindow allowing for entry of light into the eye. The periphery of thecornea (100) is known as the corneal limbus (“limbus”) (102) whichdefines the junction with the sclera (104). The limbus (102) containsstem cells for the ocular surface, contains numerous aqueous outflowpathways, and is highly vascularized.

The sclera (104) is the opaque, tough, protective, outer layer of theeye. Like the cornea it is essentially avascular. Overlying the sclera(104) is the conjunctiva (106), the thin, clear tissue that overlies thesclera (104) and the inside of the eyelids. By contributing mucus andtears, it helps lubricate the ocular surface. In addition, it isvascularized, and it helps contribute to ocular immune responses. Thespace below the conjunctiva is the subconjunctival space (122).

Posterior to the cornea, is the iris (108), or the colored part of theeye. It is an annular structure which can adjust its aperture (pupil) toregulate the amount of light entering the eye. Bright light causesconstriction of the pupil thereby limiting exposure to excessive lightor resulting glare. Under dim lighting, the pupil opens to capture moreof the available light.

The anterior chamber angle (110), which is filled with aqueous humor,resides between the iris and cornea. At its periphery, there is theanterior chamber angle (110), where aqueous drains out of the eyethrough the trabecular meshwork and Schlemm's canal.

Behind the iris (108) is the lens (112). The normal lens is transparent,and it focuses light on the retina to create a clear image. With age ordisease, the lens (112) may cloud, and this is known as cataract. Thelens (112) is suspended in the eye by fibers known as lens zonules. Oneend of the zonules attach around the equator of the lens (112). Theother end of the zonules attaches to the ciliary body (114). Contractionand relaxation of the ciliary body alter load on the zonules therebyresulting in increased curving of the lens or flattening of the lens(112). This is the primary mechanism our eyes use for focusing.

The ciliary body (114) not only contains muscles that apply load to thezonules, but it is also responsible for secreting aqueous humor whichtravels through the ciliary sulcus (116), the peripheral part of theposterior chamber. Implants or devices residing in the ciliary sulcus orperipheral posterior chamber avoid the visual axis and thus do notinterfere with vision. Aqueous humor flows into the ciliary sulcus andposterior chamber into the pupil and ultimately into the anteriorchamber (110). Research has also shown that aqueous humor currents canalso drive fluid and substances through the vitreous and through theretina. In other words, the currents are bidirectional. The posteriorchamber is the space in the eye behind the iris and in front of thelens. At its periphery, it is bounded by the ciliary sulcus (116). Theciliary sulcus (116) is the space between the front of the ciliary body(114) and the posterior surface of the iris. This part of the posteriorchamber is typically 12 mm in diameter.

The vitreous humor (118) is the gelatinous substance filling the centralcavity of the eye. Its volume is approximately 4-4.5 mL. It is boundedby the retina peripherally and posteriorly. Anteriorly, it is bounded byBerger's space, which separates the vitreous cavity from the lenscentrally and by the canal of Petit, also known as spatia zonularis,which separates it from the lens peripherally. The retina is thephotosensitive nerve layer lining the back of the eye. In humans, theretina has ten layers, with the outermost, or closest to the sclera(104), being the retinal pigment epithelium. This layer has beenimplicated in macular degeneration.

Between the sclera and the retina is a part of the uvea known as thechoroid (120). It is a high flow, low resistance vascular layer thatnourishes and oxygenates the outer two thirds of the retina. It has alsobeen implicated in macular degeneration. The macula is a region of theretina that accounts for high contrast, crisp vision. It is thefunctional center of the retina and gives humans their central vision.For example, the ability to read or recognize faces clearly is dependenton the macula. Macular degeneration affects this area, and thus can havedevastating impact on vision. The optic nerve is the coalescence ofapproximately 1 million retinal axons carrying visual information fromthe eye to vision centers in the brain.

Intraocular Implants

In general, the devices described herein comprise intraocular implantsfor treating one or more conditions of the eye by delivering one or moredrugs to the eye. The intraocular implants may comprise an implant body,such as an elongate implant body, one or more anchoring elements, and adrug. The implant body may comprise a first end and a second end and maybe configured to be positioned in the eye with the first end in thesame, or a different location, as the second end. For example, in somevariations, the implant body may be configured to be implanted withinthe eye such that the first end is positioned in the sulcus or anteriorchamber and the second end is positioned in or outside the sclera. Forexample, in some variations, the implant body may be configured to beimplanted within the eye such that the first end is positioned in thesulcus or anterior chamber and the second end is positioned in thesclera or in the subconjunctival space. In other variations, the implantbody may be configured to be positioned intramurally within the eye,such as, entirely positioned within the sclera, the cornea, the limbus,or a combination thereof.

As will be described in more detail herein, the implant body maycomprise an anchoring element configured to retain the implant withinthe eye and maintain the implant in the desired position within the eye.The anchor element may be formed from the implant body and/or may becoupled to the implant body. In some variations, the intraocularimplants described herein may comprise a plurality of anchoringelements, such as, for example, two, three, four, five, six, seven, ormore, including all ranges therein.

The intraocular implants may further comprise one or more drugs. In somevariations, the implant body may comprise the one or more drugs, suchwithin a chamber in the implant body and/or within a drug-eluting matrixforming the implant body or coating an exterior surface thereof. Inother variations, the intraocular implants may comprise a separatehousing coupled to the implant body that may contain or otherwisedeliver the drug to the eye. Regardless, the intraocular implants may bedrug-eluting or otherwise configured to deliver, administer, or provideone or more drugs to the eye.

Implant Body

In general, the implant bodies disclosed herein may be rounded (e.g.,spherical, spheroid, ovoid) and/or elongate. Elongate implant bodies maycomprise, for instance, filaments, sheets, rods, cylindrical capsules,coils, screws, and/or tubular bodies. Thus, implant bodies may have avariety of cross-sectional shapes, including, for example, circular,oval, square, and rectangular. In general, the implant body may comprisea first end and a second end and the implant body, or a portion of theimplant body, may be hollow to accommodate, for instance, a drug, asolution of a drug, a slurry of the drug, an emulsion of the drug, adrug-eluting matrix, or a drug reservoir. Thus, in some variations, theimplant body may comprise a reservoir or cavity between the first andsecond ends that contains one or more drugs. Alternatively, the implantbody, or a portion of the implant body, may be solid. In somevariations, all or a portion of the implant body may be coated with adrug-eluting matrix. For example, in some variations, the entireexternal surface of the implant body may be coated with the drug-elutingmatrix or only a portion (e.g., one third, one half, two-thirds, aproximal end or portion, a distal end or portion, or the like) of theimplant body may be coated. The implant body may have exterior orinterior surface modifications that increase adhesion of a drug ordrug-eluting matrix to the surface. In some variations, an implant bodymay have one or more sharpened, pointed, and/or triangular-shaped ends(e.g., a first end, a second end, or both first and second ends). Forexample, an implant body may be configured as a needle, for instance amicroneedle. In some variations, an implant body may be sharp,configured such that it may pierce a tissue of the eye (e.g., sclera)without the aid of a delivery device. In some instances, such implants(e.g., implants in the form of microneedles) may allow for less invasiveand/or less painful implantation than other implant designs.

In some embodiments, the implant body does not comprise a lumen for flowof aqueous humor therethrough. Put another way, in some variations, theintraocular implants described herein may not be used to shunt fluidfrom one location within the eye to another.

The implant bodies described herein may comprise a variety of materialssuitable for use in a human subject. In some embodiments, the implantbody may comprise one or more biocompatible materials, such asbiocompatible polymers or plastics, polymer composites, ceramics orceramic composites, glass or glass composites, metals, alloys (e.g.,shape-memory alloys, superelastic alloys) or combinations or derivativesof these materials. Examples of biocompatible metals and metal alloysinclude stainless steel, gold, silver, titanium, tantalum, platinum andalloys thereof, cobalt and chromium alloys, and nickel-titanium alloyssuch as Nitinol. Examples of biocompatible polymers includepoly(lactic-co-glycolic acid) (PLGA), poly(lactic acid) (PLA),poly(glycolic acid) (PGA), high density polyethylene (HDPE),poly(styrene-block-isobutylene-block-styrene) (SIBS), polyurethane,polycarbonate, polypropylene, polymethylmethacrylate (PMMA),polybutylmethacrylate, polyesters, polytetrafluoroethylene (PTFE),silicone, acrylic polymers, polyvinyl alcohol, polyvinyl pyrrolidone,polyvinyl chloride, ethyl vinyl acetate, collagen, collagen derivatives,flexible fused silica, polyolefins, NYLON® polymers, polyimide,polyacrylamide, fluorinated elastomers, and copolymers and blendsthereof. The intraocular implant or implant body may be fully orpartially erodible (e.g., biodegradable), and may, for instance,comprise poly(D,L-lactide), poly(D,L-lactide-co-glycolide),poly(D,L-lactide)acid, and polyethylene glycol 3350. Put another way, insome variations, the entire intraocular implant or the entire implantbody may be fully erodible (e.g., biodegradable). The rate of elution ofa drug from an erodible intraocular implant or implant body describedherein may be controlled by selecting an appropriate erodible material(e.g, a polymer) with predictable release characteristics (e.g., rate ofrelease). In some embodiments, the implant body may comprise an erodibledrug-eluting matrix with variable erosion rates. For example, in somevariations, a first end or portion of the implant body may have a firsterosion rate (e.g., the rate at which the drug-eluting matrix isdegraded or absorbed) and a second end or portion of the implant bodymay have a second, different erosion rate. Thus, elution of a drug froman implant or implant body described herein may have a constant orvariable rate. In some embodiments, the first erosion rate may be higherthan the second erosion rate, or vice versa. In some variations, theimplant body may comprise one or more layers, each layer comprising anerodible drug-eluting matrix. They layers may have the same erosionrates, or one or more layers may have different erosion rates. In somevariations, the implant body may contain a drug or erodible drug-elutingmatrix. In some embodiments, the implant body may comprise an erodiblematerial (e.g., polymer), the erosion rate of which can be tuned byselecting an appropriate material (e.g., polymer). In some variations,the implant body may have a first erosion rate (e.g., the rate at whichthe housing dissolves), and a drug-eluting matrix contained within mayhave a second erosion rate (e.g., the rate at which the drug-elutingmatrix is degraded or absorbed). In some embodiments, the second erosionrate may be higher than the first erosion rate. Thus, the drug may elutefaster than the housing erodes.

In some embodiments, the implant body may be a needle or microneedle. Insome embodiments the needle or microneedle may have a length that issimilar or equal to the thickness of the sclera (e.g., 0.5 mm to 1 mm),such that it may fully reside in the sclera. In some variations, theneedle or microneedle may have a length that is greater than thethickness of the sclera, or less than the thickness of the sclera. Insome embodiments, the implant body may extend from the sclera into theanterior chamber, sulcus, or posterior chamber. In some embodiments, aneedle or microneedle implant body may be biodegradable, as describedherein.

In some embodiments, the implant body may comprise a filament or suture.The implant body may, for instance, comprise a filament or suturecomprising a polymer. The filament or suture may comprise a single fiberor may comprise a plurality of fibers, such as, for example, a pluralityof braided fibers. In some variations, it may be useful to utilize afilament or suture with braided fibers to strengthen the filament orsuture against breakage by mechanical force, such as, during extractionof the implant from the eye. In certain embodiments, the filament orsuture may comprise polytetrafluoroethylene (PTFE), polypropylene,polyimide, polyester, or nylon.

In some variations, an implant body configured for placement within theeye may comprise a spherical or rod-shaped implant body configured to bepositioned entirely in the sclera. In these variations, the spherical orrod-shaped implant body may comprise an erodible drug-eluting matrixand/or a reservoir containing a drug or drug-eluting matrix. In somevariations, all or a portion of the spherical or rod-shaped implant bodymay be coated with a drug-eluting matrix. In certain variations, thespherical or rod-shaped implant body may comprise an exterior shell andan interior chamber. The interior chamber may accommodate, for instance,a drug, a solution of a drug, a slurry of the drug, an emulsion of thedrug, a drug-eluting matrix, or a drug reservoir. In some variations,the implant body may comprise fenestrations in the shell or the shellmay be porous to deliver a drug from the interior chamber of the implantbody to the eye.

The implant bodies described here may be configured for placement withinthe eye. For example, the implant bodies may comprise a size and shapesuitable for placement and retainment within one or more structures ofthe eye. For example, in some variations, the implant body may residepartially in the sclera with a first end residing in the sulcus,vitreous, or anterior chamber and a second end residing in thesubconjunctival space. In certain variations, the implant body mayreside partially in the sclera with a first end residing in the sulcus,vitreous, or anterior chamber and a second end residing in the sclera.In some variations of the implant bodies described herein, when aportion of the implant resides in the anterior chamber, said portion mayreside in the iridocorneal angle. For instance, in some variations, theimplant body may reside partially in the sclera, cornea, or limbus(e.g., a second end residing in the sclera, cornea, or limbus) with afirst end residing in the iridocorneal angle.

In certain variations, the implant body may reside fully within thecornea, such as, for example, with a first end and a second end residingin the cornea. In certain variations, the implant body may reside fullywithin the sclera, such as, for example, with a first end and a secondend residing in the sclera. In certain variations, the implant body mayreside partially within the limbus (e.g., the implant body traverses thelimbus), with a first end residing in the cornea, a central portionresiding in the limbus, and a second end residing in the sclera. Incertain variations, the implant body may reside partially within thelimbus, with a first end residing in the sclera, a central portionresiding in the limbus, and a second end residing in the cornea. Incertain variations, the implant body may reside fully intramurally, witha first end residing in the limbus and a second end residing in thesclera. In certain variations, the implant body may reside fullyintramurally, with a first end residing in the sclera and a second endresiding in the limbus. In certain variations, the implant body mayreside fully intramurally, with a first end residing in the limbus and asecond end residing in the cornea. In certain variations, the implantbody may reside fully intramurally, with a first end residing in thecornea and a second end residing in the limbus. In some variations, theimplant body may reside fully within the suprachoroidal space. In somevariations, the implant body resides partially within the suprachoroidalspace and partially within the sclera (e.g., a first end in thesuprachoroidal space and a second end in the sclera, or a first end inthe sclera and a second end in the suprachoroidal space). In somevariations, the implant body resides partially within the suprachoroidalspace and partially within the anterior chamber (e.g., a first end inthe suprachoroidal space and a second end in the anterior chamber, or afirst end in the anterior chamber and a second end in the suprachoroidalspace). In some variations, the implant body is spherical or rod-shapedand resides fully within the sclera, cornea, or limbus.

In some variations, the implant body of the intraocular devices (e.g.,an implant, a drug-eluting implant) described herein may comprise alength (or major axis) or width (or minor axis) of between about 10 μmand about 20 mm. In some embodiments, the implant body of theintraocular implants described herein may comprise a length (or majoraxis) or width (or minor axis) of between about 0.1 mm and about 20 mm,between about 0.1 mm and about 5 mm, between about 0.1 mm and about 4mm, between about 0.1 mm and about 3 mm, between about 0.1 mm and about2 mm, between about 0.1 mm and about 1.5 mm, between about 0.1 mm andabout 1 mm, between about 0.1 mm and about 0.5 mm, between about 0.5 mmand about 5 mm, between about 0.5 mm and about 4 mm, between about 0.5mm and about 3 mm, between about 0.5 mm and about 2 mm, between about0.5 mm and about 1 mm, between about 1.0 mm and about 5.0 mm, betweenabout 1.0 mm and about 4.0 mm, between about 1 mm and about 3 mm,between about 1 mm and about 2 mm, between about 1 mm and about 1.5 mm,between about 1 mm and about 20 mm, between about 2 mm and about 20 mm,between about 2 mm and about 18 mm, between about 2 mm and about 16 mm,between about 2 mm and about 14 mm, between about 2 mm and about 12 mm,between about 2 mm and about 10 mm, between about 2 mm and about 8 mm,between about 2 mm and about 6 mm, between about 2 mm and 4 mm, betweenabout 4 mm and about 20 mm, between about 4 mm and about 18 mm, betweenabout 4 mm and about 16 mm, between about 4 mm and about 14 mm, betweenabout 4 mm and about 12 mm, between about 4 mm and about 10 mm, betweenabout 4 mm and about 8 mm, between about 4 mm and about 6 mm, betweenabout 6 mm and about 20 mm, between about 6 mm and about 18 mm, betweenabout 6 mm and about 16 mm, between about 6 mm and about 14 mm, betweenabout 6 mm and about 12 mm, between about 6 mm and about 10 mm, betweenabout 6 mm and about 8 mm, between about 8 mm and about 20 mm, betweenabout 8 mm and about 18 mm, between about 8 mm and about 16 mm, betweenabout 8 mm and about 14 mm, between about 8 mm and about 12 mm, betweenabout 8 mm and about 10 mm, between about 10 mm and about 20 mm, betweenabout 10 mm and about 18 mm, between about 10 mm and about 16 mm,between about 10 mm and about 14 mm, between about 10 mm and about 12mm, between about 12 mm and about 20 mm, between about 12 mm and about18 mm, between about 12 mm and about 16 mm, between about 12 mm andabout 14 mm, between about 14 mm and about 20 mm, between about 14 mmand about 18 mm, between about 14 mm and about 16 mm, between about 16mm and about 20 mm, between about 16 mm and about 18 mm, or betweenabout 18 mm and about 20 mm (including all sub-ranges and valuestherein). In some embodiments, the implant body length or width of theintraocular devices described herein may be about 1 mm, about 1.5 mm,about 2 mm, about 3 mm, about 4 mm, about 5 mm, about 6 mm, about 7 mm,about 8 mm, about 9 mm, about 10 mm, about 11 mm, about 12 mm, about 13mm, about 14 mm, about 15 mm, about 16 mm, about 17 mm, about 18 mm,about 19 mm, or about 20 mm (including all sub-ranges and valuestherein).

In some variations, a portion of an implant residing within a cavity ofthe eye (e.g., anterior chamber, posterior chamber (e.g., sulcus)) maycomprise a length (or major axis) of between about 0.1 mm and 5 mm,between about 0.1 mm and 0.5 mm, between about 0.1 mm and 1 mm, betweenabout 0.1 mm and 4 mm, between about 0.1 mm and 3 mm, between about 0.1mm and 2 mm, between about 0.1 mm and 1.5 mm, between about 0.5 mm and 5mm, between about 0.5 mm and 4 mm, between about 0.5 mm and 3 mm,between about 0.5 mm and 2 mm, between about 0.5 mm and 1 mm, betweenabout 1 mm and 5 mm, between about 1 mm and 4 mm, between about 1 mm and3 mm, between about 1 mm and 2 mm, between about 2 mm and 5 mm, betweenabout 2 mm and 4 mm, between about 2 mm and 3 mm, between about 3 mm and5 mm, between about 3 mm and 4 mm, or between about 4 mm and 5 mm(including all sub-ranges and values therein). In some embodiments, theimplant body of the intraocular devices described herein may be about0.1 mm, about 0.5 mm, about 1 mm, about 1.5 mm, about 2 mm, about 3 mm,about 4 mm, or about 5 mm.

In some variations, a portion of an implant or implant body residingpartially intramurally (e.g., cornea, sclera, limbus), or an implantresiding wholly intramurally (e.g., cornea, sclera, limbus), maycomprise a length (or major axis) of between about 0.1 mm and about 10mm, between about 0.1 mm and about 5 mm, between about 0.1 mm and about4 mm, between about 0.1 mm and about 3 mm, between about 0.1 mm andabout 2 mm, between about 0.1 mm and about 1.5 mm, between about 0.1 mmand about 1 mm, between about 0.1 mm and about 0.5 mm, between about 0.5mm and about 5 mm, between about 0.5 mm and about 4 mm, between about0.5 mm and about 3 mm, between about 0.5 mm and about 2 mm, betweenabout 0.5 mm and about 1 mm, between about 1 mm and about 1.5 mm,between about 1 mm and about 5.0 mm, between about 1 mm and about 4.0mm, between about 1 mm and about 3 mm, between about 1 mm and about 2mm, between about 1 mm and about 10 mm, between about 2 mm and about 10mm, between about 2 mm and about 8 mm, between about 2 mm and about 6mm, between about 4 mm and about 10 mm, between about 4 mm and about 8mm, between about 4 mm and about 6 mm, between about 6 mm and about 10mm, between about 6 mm and about 8 mm, between about 8 mm and about 10mm. In some embodiments, the implant body of the intramural intraoculardevices described herein may be about 1 mm, about 1.5 mm, about 2 mm,about 3 mm, about 4 mm, about 5 mm, about 6 mm, about 7 mm, about 8 mm,about 9 mm, or about 10 mm (including all sub-ranges and valuestherein).

In some embodiments, the implant body of the intraocular implant orimplant bodies described herein have a width (or minor axis) of about0.1 mm, 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm, 1.0 mm, 2.0 mm, or 3.0 mm. Insome embodiments, the implant or implant body of the intraocular devicesmay have a width (or minor axis) of between about 0.1 mm and about 2 mm,between about 0.1 mm and about 1.5 mm, between about 0.1 mm and about1.0 mm, between about 0.1 mm and about 0.5 mm, between about 0.5 mm andabout 2 mm, between about 0.5 mm and about 1.5 mm, between about 0.5 mmand about 1.0 mm, between about 1.0 mm and about 2.0 mm, between about1.0 mm and about 1.5 mm, between about 1.5 mm and about 2.0 mm, betweenabout 0.25 mm and about 1.0 mm, between about 0.1 mm and about 0.5 mm,or between about 0.2 mm and about 0.3 mm (including all sub-ranges andvalues therein). In certain embodiments, the implants or implant bodiesdescribed herein may have a widths of about 0.1 mm, 0.2 mm, 0.3 mm, 0.4mm, or 0.5 mm.

In some embodiments, the implant body of the intraocular devicesdescribed herein are spheres, spheroids, or ovoids, and may have adiameter (or minor axis) of about 0.1 mm, 0.2 mm, 0.3 mm, 0.4 mm, 0.5mm, 1.0 mm, 2.0 mm, or 3.0 mm. In some embodiments, the implant body ofthe intraocular devices may have a diameter (or minor axis) of betweenabout 0.1 mm and about 2 mm, between about 0.1 mm and about 1.5 mm,between about 0.1 mm and about 1.0 mm, between about 0.1 mm and about0.5 mm, between about 0.5 mm and about 2 mm, between about 0.5 mm andabout 1.5 mm, between about 0.5 mm and about 1.0 mm, between about 1.0mm and about 2.0 mm, between about 1.0 mm and about 1.5 mm, betweenabout 1.5 mm and about 2.0 mm, between about 0.25 mm and about 1.0 mm,between about 0.1 mm and about 0.5 mm, or between about 0.2 mm and about0.3 mm (including all sub-ranges and values therein). In certainembodiments, the implants or implant bodies described herein may have adiameter (or minor axis) of about 0.1 mm, 0.2 mm, 0.3 mm, 0.4 mm, or 0.5mm.

By way of example, an implant body positioned in a tissue of the eye(e.g., sclera) may be coated with a drug or drug-eluting matrix betweenthe first end of the implant body and the tissue. In some instances, animplant body positioned in a tissue of the eye (e.g., sclera) may becoated with a drug or drug the entire length of the implant (i.e.,between the first end and the second end). Accordingly, an implant bodypositioned in a tissue may only be coated with drug on the portion ofthe implant body between the first end and the tissue (e.g., the portionfully within the sulcus, fully within the anterior chamber, or fullywithin the vitreous cavity). In the case of an intraocular implantcomprising a housing, the interior, exterior, or both interior andexterior portions of the housing may be coated or filled with a drug ordrug-eluting matrix.

The drug-eluting implant may be any suitable size or shape to securelyreside at least partially within a limbus of the eye without extendinginto the anterior chamber. In some variations of the methods describedherein, the drug-eluting implant comprises an elongate implant bodycomprising a first and a second end. The elongate implant body may, forinstance be cylindrical, a rectangular prism, a sheet, or any othersuitable shape described herein

Because the implant bodies described herein may be designed to beremovable, in some variations, an implant body may be configured to beretrieved from the eye and may additionally comprise a removal featureconfigured to be grasped for removal of the implant from the eye. Forexample, in some variations, the removal feature may comprise a wire,filament, suture, tab, or other structure coupled to the implant body orhousing. In these variations, methods may comprise engaging the removalfeature of the intraocular implant with an instrument (e.g., forceps)and removing the implant from the eye using the removal feature. In somevariations, an implant body (e.g., filament, suture) is also a removalfeature. The removal feature may be configured to be positioned in atissue of the eye (e.g., embedded in the sclera, cornea, or limbus) ormay be configured to be positioned either partially or wholly outside ofa tissue of the eye (e.g., in the subconjunctival space)

Anchoring Elements

An intraocular implant for treating a condition of the eye may furthercomprise at least one anchoring element coupled to, or formed from, theimplant body. The anchoring element may be any structural featuresuitable for holding the intraocular implant in place, preventing theimplant body from becoming dislodged from a portion of the eye (e.g.,from the sclera, the cornea, the limbus, the sulcus). In variations inwhich the intraocular implant is implanted partially in the sulcus, theanchoring element may prevent the implant from falling entirely into thesulcus or entirely into the subconjunctival space. Anchoring elementsmay be present on any portion of the implant body, including any portionof the implant body residing within the sclera, within the sulcus,between the first end of the elongate implant body and the sclera, orwithin the subconjunctival space. Suitable anchoring elements maycomprise knots, beads, barbs, crossbars, heads, enlarged (e.g., rounded)or extended portions of an implant body, or any other feature configuredto maintain placement and/or orientation of an intraocular implantand/or implant body within the eye.

Anchoring elements may be expandable such that they remain folded orstowed prior to implantation and/or during removal of the implant fromthe eye and deploy upon implantation. For example, one or more anchoringelements may have a first compressed or low-profile, undeployedconfiguration or position and a second expanded, deployed configurationor position. The anchoring elements may be in the first, undeployed,position during advancement of the intraocular implants into the desiredposition in the eye, and the anchor elements may transition to thedeployed position during or after implantation (e.g., during or afterrelease of the implants from a delivery device). Upon proper positioningof the implant, the anchoring elements may be in the expanded, deployedconfiguration and may assist in securing the implant in the appropriatelocation, position and orientation. In some variations, expandableanchoring elements may comprise barbs (e.g., with sharpened distal tips)or crossbars, which may extend from the elongate implant body when inthe expanded configuration. The barbs and/or crossbars may extend fromthe implant body at any suitable angle relative to a longitudinal axisof the implant body, such as, for example, between 20 degrees and 160degrees, including all values and sub-ranges therein. In somevariations, the barbs and/or crossbars may extend at about a 45 degree,about a 90 degree, or between about a 45 degree and about a 90-degreeangle relative to the longitudinal axis of the implant body. Anchoringelements may be comprised of shape-memory metal, shape-memory alloys, orshape-memory polymers which may change shape upon delivery (e.g., expandto secure the position of the implant body). An anchoring element mayexpand upon delivery due to fluid absorption. Anchoring elements mayadditionally be erodible. In some embodiments comprising erodibleanchoring elements, the erodible anchoring elements may erode at adifferent rate (e.g., faster, slower) than another erodible element ofthe intraocular implant (e.g., a housing).

In some instances, an anchoring element may be a portion of the implantbody. For example, in some variations, the anchoring element may be anenlarged portion of the implant body (e.g., a thread or suture). Forexample, the first end of the implant body may be larger (e.g., indiameter or in width) than a central portion and/or second end of theimplant body and/or a second end of the implant body may be larger(e.g., in diameter or in width) than a central portion and/or a firstend of the implant body. In some variations, both ends of the implantbody may be larger than a central portion of the implant body. Putanother way, one or both ends of the implant body may be deliberatelyenlarged to minimize potential movement. Additionally, in someembodiments, the enlarged portion(s) (e.g., enlarged first end, enlargedsecond end) may be fully erodible. Having an enlarged portion/anchoringelement that is fully erodible may be advantageous as it may allow foreasier removal of the remainder of the implant body once the erodibleportion has fully dissolved (e.g., the intraocular implant can beretrieved by a non-erodible portion of the implant body or othernon-erodible portion of the intraocular implant). In some variations,the anchoring element may be a portion of the implant body that changesshape upon implantation/delivery to the eye, and/or that expands uponimplantation/delivery to the eye (e.g., by gaining moisture). Invariations comprising a portion of the implant body that serves as ananchoring element (e.g., one or more enlarged ends, shape-changingportion, expanding portion), the anchoring element (e.g., more enlargedends, shape-changing portion, expanding portion) may reside in any ofthe locations described herein, such as, for example, in the sulcus, theanterior chamber, the cornea, the sclera, the limbus, or thesubconjunctival space.

In some variations, the implant body may not comprise an anchoringelement and the entire implant body may be used to anchor theintraocular implant. For example, in some variations, the entire implantbody may expand (e.g., by gaining moisture) to secure the implant inplace. Additionally or alternatively, the implant body, and thus theintraocular implant, may be secured by positioning the implant or aportion of the implant (e.g., the implant body) within a channel orcavity created in a tissue prior to implantation that has a smallerdiameter or width than the diameter or width of the portion of theimplant positioned therein after implantation (e.g., implant body).

In some variations, an intraocular implant may comprise a plurality ofanchoring elements. For example, in some variations, the intraocularimplant may comprise two, three, four, five, six, or more anchoringelements, each of which may assist in retaining the intraocular implantin the appropriate position and orientation within the eye. In thesevariations, the plurality of anchoring elements may be the same, or oneor more of the anchoring elements may be different from one or more ofthe remaining anchoring elements. Each anchoring element may beindependently positioned on any portion of the implant body in order toprevent the implant body from becoming dislodged (e.g., from thesclera). Utilizing multiple anchoring elements may, for instance, allowfor precisely controlling the depth or location of implantation of theintraocular implant. Suitable positions for the anchoring elementsinclude, for instance, at a first end of the implant body, at a secondend of the implant body, on a proximal portion of the implant body, on adistal portion of the implant body, between the first and second ends ofthe implant body (e.g., equally or unequally spaced along a length ofthe implant body). In some variations, one or more of the anchoringelements may be positioned along the implant body a distancecorresponding to the thickness of the sclera such that one or moreanchoring elements may be positioned on one side of the sclera and oneor more anchoring elements may be positioned on the opposite side of thesclera.

In use, one or more anchoring elements may be positioned in variousportions of the eye. For example, in some variations, one or more of theanchoring elements may be positioned within the sclera. In somevariations, one or more of the anchoring elements may be positioned inthe subconjunctival space. In some variations, one or more of theanchoring elements may be positioned in the suprachoroidal space. Invariations in which one or more anchoring elements is positioned along alength of the implant body (i.e., between the ends of the implant body),once implanted, one or more anchoring elements may be positioned along alength of the implant body between the first end of the implant body andthe sclera and/or along a length the implant body between the sclera andthe second end of the implant body.

When a plurality of anchoring elements is employed, the anchoringelements may be positioned within the same structure in the eye (e.g.,the sclera) or within different structures in the eye (e.g., one or morein the sclera, one or more in the subconjunctival space). For example,in some embodiments, one or more anchoring element may be positionedwithin the sclera and one or more other anchoring elements may bepositioned between the first end or second end of the implant and thesclera. In some instances, one or more anchoring elements may bepositioned between the second end of the implant body and the sclera andone or more other anchoring elements may be positioned between the firstend of the elongate implant body and the sclera. In some embodiments,the at least one anchoring element comprises a plurality of beads orbarbs positioned along a length of the implant body. A plurality ofbeads of barbs may serve to simultaneously anchor the elongate implantbody at multiple locations (i.e., in the subconjunctival space, withinthe sclera, and in the sulcus). A plurality of anchoring element mayalso be used for intraocular implants positioned entirely intramurally.For instance, for implant bodies positioned entirely within the cornea,one or more anchoring elements may be positioned along the implant bodyentirely within the cornea. In some embodiments, the implant body may bepositioned partially in the cornea and partially in the limbus, and oneor more anchoring elements may be positioned along the portion of theimplant body within the cornea and/or the portion of the implant bodywithin the limbus. In some embodiments, the implant body may bepositioned partially in the sclera and partially in the limbus, and oneor more anchoring elements may be positioned along the portion of theimplant body within the sclera and/or the portion of the implant bodywithin the limbus. In some embodiments, the implant body may bepositioned partially in the cornea, partially in the limbus, andpartially in the sclera, and one or more anchoring elements may bepositioned along the portion of the implant body within the scleraand/or the portion of the implant body within the limbus and/or theportion of the implant body within the cornea. In some embodiments, theimplant body may be positioned fully in the suprachoroidal space, andone or more anchoring elements may be positioned along the portion ofthe implant body within the suprachoroidal space. In some embodiments,the implant body may be positioned partially in the suprachoroidal spaceand partially in the anterior chamber, and one or more anchoringelements may be positioned along the portion of the implant body withinthe suprachoroidal space and/or along the portion of the implant bodywithin the anterior chamber.

Housing

The intraocular implant described herein may further comprise a separatehousing coupled to the implant body (such as, for example, to an end ofthe implant body), that is configured to deliver one or more drugs tothe eye. The housing may take any form suitable for delivery of drug tothe eye, such as, for example, a canister, a coil, a bag, and/or a cage.The housing may comprise a shell with a cavity or interior chambercontaining one or more drugs, may be formed from a drug-eluting matrix,and/or an external surface of the housing may be coated with adrug-eluting matrix. In some variations, the housing may be a canistercomprising a shell and a hollow interior chamber. The interior chambermay accommodate, for instance, a drug, a solution of a drug, a slurry ofthe drug, an emulsion of the drug, a drug-eluting matrix, or a drugreservoir. The canister may have any suitable cross-sectional shape,such as, for example, circular, oval, square, triangular or the like.

In variations comprising an interior chamber, to facilitate the releaseof drug, the housing may comprise one or more openings from which drugmay elute from the interior chamber and/or the housing may be porous(e.g., made from a material porous to the drug). For example, in somevariations, the housing may comprise fenestrations in the shell or theshell may be porous to deliver a drug from the interior chamber of thehousing to the eye. The size, shape, and quantity of fenestrationsand/or the porosity may be selected to achieve a desired drug releaseprofile. In some variations, the housing may comprise a porous bag. Insome instances, the housing may comprise first and second ends, and oneor both of the ends may be open such that drug may be delivered throughthe open end(s). In variations comprising an interior chamber, both endsmay be closed, such that drug is delivered through openings in theshell, and/or one or both ends may be open such that drug is deliveredeither through one or both ends, or through one or both ends andopenings in the shell. In some embodiments, one or both ends of thehousing may be partially closed and partially open. For example, a firstend of the housing may comprise a first opening and/or a second end ofthe housing may comprise a second opening. In variations in which thehousing comprises a canister, the canister may comprise a first canisterend and a second canister end. The first and second canister ends mayeach be open or have openings, may each be closed, and the canister bodyor shell may have openings, or either end may be open or have openingswhile the other end is closed. Any of the aforementioned openings may besealed with a membrane permeable or semi-permeable to the drug.

In some embodiments, the housing may comprise a non-erodible housing. Insome embodiments, the housing may comprise a non-erodible housing thatis coated or filled with a drug-eluting matrix. The drug eluting matrixmay be erodible or non-erodible. For instance, in some variations, thehousing may comprise a non-erodible bag, sac, cage, or canister thatcontains a drug or erodible drug-eluting matrix. In some variations, thehousing may comprise an erodible bag, sac, cage, canister, or othercontainer that contains a drug or erodible drug-eluting matrix. In someembodiments, the housing may comprise an erodible material (e.g.,polymer), the erosion rate of which can be pre-determined by selectingan appropriate material (e.g., polymer). In some variations, the housingmay have a first erosion rate (e.g., the rate at which the housingdissolves), and a drug-eluting matrix contained within the housing mayhave a second erosion rate (e.g., the rate at which the drug-elutingmatrix is degraded or absorbed). In some embodiments, the second erosionrate may be higher than the first erosion rate. Thus, the drug may elutefaster than the housing erodes.

As described herein, the housing may be attached to the implant body inany suitable orientation. For instance, the elongate implant body maycomprise a first longitudinal axis and the housing may comprise a secondlongitudinal axis. In some variations, the housing may be coupled to theimplant body such that the first longitudinal axis is parallel with thesecond longitudinal axis., while in other variations, the housing may becoupled to the implant body such that the first longitudinal axis istransverse to the second longitudinal axis. An intraocular implantcomprising an implant body and a housing with parallel longitudinal axesis depicted in FIG. 2H and an intraocular implant comprising an implantbody and a housing with transverse longitudinal axes is depicted in FIG.2I. In variations in which the longitudinal axes are transverse, theangle between the longitudinal axes may be, for example, about 90degrees, between about 85 and about 90 degrees, between about 80 andabout 85 degrees, etc.

When intraocular implants comprise a housing, the housing may bepositioned in any location described herein to which delivery of drug isdesired. For example, the housing may be positioned inside the sulcus oranterior chamber, or within a mural tissue or combination of muraltissues (e.g., sclera, limbus, cornea).

In some variations, the intraocular implants described herein may berefillable (or a reservoir containing the drug contained therein may bereplaceable) so that a single intraocular implant may provide treatmentfor a longer duration. For example, in some variations, an intraocularimplant (e.g., implant body, housing) may comprise a refillable orreplaceable reservoir (e.g., coupled or attached to an implant body,within an implant body, within a housing) containing the drug. Thus,once the bolus of drug initially contained within the intraocularimplant at implantation has eluted to or otherwise been delivered to theeye, the reservoir may be refilled with a second bolus of drug orreplaced with a second reservoir containing a second bolus of drug. Insome variations, the first bolus of drug may be the same as the secondbolus of drug, while in other variations, the first and second (orsubsequent) boluses of drug may be different (e.g., may containdifferent active ingredients, may contain different volumes of drug,etc.). The drugs in the intraocular implants described herein may bereplaced and/or refillable any suitable number of times, such as, forexample, two, three, four, five or more. Additionally, the drugs may bereplaced and/or refilled in-situ (e.g., while the intraocular implantremains positioned within the eye), or the intraocular implant may beremoved from the eye, the drug may be refilled or replaced, and theintraocular implant may be re-inserted into the eye. In variations inwhich the intraocular implant (e.g., implant body, housing) isrefillable, the intraocular implant may be refilled, for instance, byinjecting a drug, drug-eluting matrix, drug slurry, or the like byneedle through a port, opening, or fenestration. For instance, animplant may be refilled from a syringe, catheter, or the like undertopical anesthesia.

In some cases, it may be advantageous for the drug of the intraocularimplants described herein to be integrated into a material forming aportion of the intraocular implant (e.g., implant body, housing) suchthat the intraocular implant comprises a drug-eluting matrix. As usedherein, a “drug-eluting matrix” refers to a material impregnated with adrug, where the drug is released from the material when positionedwithin the eye. In some variations, the drug may be released slowly fromthe material over a set period of time. The drug-eluting matrix may, forinstance, comprise a polymer impregnated with the drug, where the drugis released from the polymer while implanted within the eye. In certainembodiments, the drug-eluting matrix may be erodible such that itdissolves or disintegrates within a predetermined period of time insidethe subject, safely, into non-toxic or biocompatible components. Thedrug-eluting matrices described herein may form a coating on, or afiller within, a structure of the intraocular implants described herein.For instance, in some embodiments, the implant body may comprise ahollow interior chamber containing the drug-eluting matrix and theimplant body may further comprise fenestrations (e.g., openings) througha wall of the implant body to deliver the drug from the drug-elutingmatrix in the interior chamber to the eye. Additionally oralternatively, all or a portion of the intraocular implant may comprisea drug-eluting matrix in the form of a coating. For instance, in someembodiments, the intraocular implants may comprise a coating on only afirst portion of the implant (e.g., on only the implant body, on only aportion of the implant body, on only a housing, on only a portion of ahousing) and a second portion of the implant may remain uncoated (e.g.,a second portion of the implant body, a portion of the housing). In someembodiments, the first portion of the implant is between the first endof the implant body and the sclera

Drugs

The intraocular implants may comprise one or more drugs (e.g., two,three, four, five, or more) useful for treating the condition of theeye. In some embodiments, the condition of the eye may be glaucoma, AMD,retinal diseases (e.g., retinal vascular disease), nerve disease,corneal disease, lens diseases, uvea diseases, vitreous diseases,surface diseases, lid diseases, or ocular infections. In someembodiments, the drug may comprise a drug suitable for treatingglaucoma, and diseases of the retina, lens, cornea, uvea, vitreous,iris, ciliary body, sclera, or ocular surface. Such drugs include, butare not limited to, steroids (e.g., prednisolone, prednisone, cortisone,cortisol, triamcinolone, or shorter acting steroids), anti-VEGF agents,prostaglandins, nitric oxide-releasing drugs, nitric oxide donors, betablockers, miotics, carbonic anhydrase inhibitors, ROCK inhibitors,parsympathomimetics, sympathomimetics, alpha 2 adrenergic agonists,antimetabolites (e.g., fluoruracil mitomycin C), antibiotics, steroids,non-steroidal anti-inflammatory drugs (NSAIDs), antifungals,immunosuppressants (e.g., cyclosporine), vitreous hemorrhage drugs,collagenases, vitreous floater treatments, pupil dilators, pupilconstrictors, heparin, other anticoagulants, fibrinolytic compounds, andmonoclonal antibodies or other biologics. In certain embodiments, thedrug is a nitric oxide-releasing drug in combination with aprostaglandin or other glaucoma drug (e.g., to target multiplemechanisms of action). In certain embodiments, the drug is useful forlowering intraocular pressure. In certain embodiments, the drug maysuppress production of aqueous humor. In some embodiments, the drug mayincrease the drainage of aqueous humor through a trabeculocanalicularpathway and/or a uveoscleral pathway. In some embodiments, the drug islatanoprost, travoprost, bimatoprost, ranibizumab, aflibercept,bevacizumab, brolucizumab, riboflavin, unoprostone, or corticosteroid.

As described below, drugs suitable for delivery by the implantsdescribed herein may diffuse from the location of implantation in onetissue of the eye (e.g., sclera, cornea, limbus) to another location inthe eye (e.g., anterior chamber, posterior chamber). To enhance thisdiffusion from the implant location to another location in the eye, thedrugs described herein may be administered together with the applicationof one or more penetration enhancers. Penetration enhancers may include,for instance, compounds such as cyclodextrins, chelating agents, crownethers, bile acids, bile salts, surfactants, cell-penetrating peptides,and amphiphilic compounds. Such penetration enhancers may be combinedwith the drug to treat a condition of the eye being administered by anintraocular implant described herein, or they may be administeredseparately. In some variations, a first intraocular implant delivers adrug to treat a condition of the eye, and a second intraocular implantdelivers a penetration enhancer. In other variations, one intraocularimplant delivers both a drug to a treat a condition of the eye and apenetration enhancer. Penetration enhancers may also be non-compoundpenetration enhancers, which are applied separately and in addition tothe implant. For instance, a non-compound penetration enhancer mayinclude electrical currents, iontophoresis, ultrasound, or microneedles.These may, for instance, be applied to a tissue of the eye to increasepenetration of a drug delivery by an intraocular implant describedherein. Selection of the appropriate penetration enhancer may dependupon the properties of the drug being administered (e.g., molecularweight, hydrophobicity/lipophilicity). An appropriate penetrationenhancer may be selected for enhancing penetration of a drug through aspecific tissue (e.g., cornea, sclera).

Currently available treatments for eye disorders such as glaucoma usemedicated drops that persist for less than 24 hours. For AMD and retinaldiseases, certain other ocular injections provide delivery of drugs toeye tissues for a few weeks or a few months. In contrast, theintraocular implants described herein allow for the continuous orsemi-continuous delivery of one or more drugs for days or weeks, and/ormonths or years. In some embodiments, the drug is delivered to the eyeover a predetermined period of time, such as, for example, over at leastabout 1, 2, 3, 6, 9, 12, 18, 24, 30, 36, 48, 60, or 72 months (includingall values and sub-ranges therein). For example, in some variations, theintraocular implant is configured to for sustained-release of drug tothe eye for between about 1 month and about 3 months, about 2 months andabout 4 months, about 1 month and about 6 months, about 6 months andabout 9 months, about 6 months and about 12 months, about 12 months andabout 18 months, about 12 months and about 24 months, about 24 monthsand about 36 months, about 12 months to about 72 months or about 1 monthto about 72 months. In certain embodiments, the period of time is atleast about 1 year, 5 years, 10 years, 15 years, 20 years or betweenabout 1 year and about 5 years, about 1 year and about 10 years, about 5years and about 10 years, about 5 years and about 15 years, about 10years and about 20 years, about 5 years and about 20 years or about 1year and about 20 years.

The implants described herein may be biodegradable. In some variations,one or more implants may be delivered to one or more tissues of the eyewhen one or more implants degrades within the eye. For instance, a newimplant may replace a partially or fully degraded implant every month,every 3 months, every 6 months, every 12 months, every 18 months, every2 years, every 3 years, or more, or at any interval therein.

As discussed previously, in variations in which the intraocular implantis positioned at least partially within the sulcus, the drug deliveredfrom the intraocular implant may be taken up by anterior and/orposterior flowing currents such that it may be delivered to the anteriorand/or posterior chambers of the eye. In these variations, an end of theimplant body (e.g., first end, second end) may be configured to elutedrug (e.g., may have a drug-eluting coating, may have one or moreopenings to allow for delivery of drug from within the implant body) andthis end may be positioned within the sulcus. In some variations, thedrug may be delivered to the anterior chamber, the posterior chamber(e.g., the sulcus and/or remainder of the posterior chamber), thecornea, the iris, the lens, the pupil, the cornea, the retina, or thevitreous body. In variations in which the intraocular implant ispositioned intramurally, the drug may be delivered through the sclera tothe anterior chamber, through the sclera to the posterior chamber,through the cornea to the anterior chamber, through the cornea to theposterior chamber, through the limbus to the anterior chamber, orthrough the limbus to the posterior chamber.

Implant Locations

Intraocular implants may reside in a tissue of the eye, wherein animplant body resides at least partially in the sclera, and a first endof an implant body resides in the posterior chamber (e.g., within thesulcus, within the sulcus and partially extending into the remainder ofthe posterior chamber), anterior chamber, Berger's space, Canal ofPetit, or Canal of Hannover. For example, in some variations, theimplant body may reside partially in the sclera with a first endresiding in the sulcus or anterior chamber and a second end residing inthe subconjunctival space (e.g., the implant body traverses the sclera).In certain variations, the implant body may reside partially in thesclera with a first end residing in the sulcus or anterior chamber and asecond end residing in the sclera (e.g., the implant body does notreside in the subconjunctival space). In some variations, the implantbody may reside partially in the sclera with a first end residing inBerger's space, the Canal of Petit, or the Canal of Hannover, and asecond end residing in the subconjunctival space (e.g., the implant bodytraverses the sclera). In certain variations, the implant body mayreside partially in the sclera with a first end residing in Berger'sspace, the Canal of Petit, or the Canal of Hannover, and a second endresiding in the sclera. It should be understood that intraocularimplants or implant bodies described herein as positioned in or residingwithin the sulcus may or may not extend out of the sulcus into theremainder of the posterior chamber. For example, in some variationsimplant bodies positioned or residing within the sulcus may have an endpositioned within the sulcus such that the implant body does not extendbeyond the sulcus into the remainder of the posterior chamber. Forexample, in some variations, implants may only extend less than about 1mm, less than about 0.5 mm, about 0.5 mm, about 1.0 mm, or between about0.5 mm and about 1.0 mm into the sulcus and does not extend beyond thesulcus into the remainder of the posterior chamber.

In other variations, implant bodies positioned or residing within thesulcus may traverse or partially reside in the sulcus but may extendinto the remainder of the posterior chamber such that an end of theimplant body resides just beyond the sulcus in the posterior chamber.For example, in some variations, implants may only extend less thanabout 2 mm, less than about 1 mm, less than about 0.5 mm, less thanabout 0.25 mm, between about 2 mm and about 0.25 mm, between about 2 mmand about 0.5 mm, between about 2 mm and about 1 mm, between about 1 mmand about 0.25 mm, between about 1 mm and about 0.5 mm, or between about0.5 mm and about 0.25 mm beyond the sulcus into the posterior chamber.

The intraocular implants or portions thereof (e.g., implant bodies,housings) described herein may be positioned such that they avoiddamaging endothelial cells. Implants may, for instance, be positionedpartially within the posterior chamber (e.g., within the sulcus, withinthe sulcus and partially extending into the remainder of the posteriorchamber) as described in greater detail herein. Implants may also bepositioned partially within the anterior chamber, however, implantspositioned partially in the anterior chamber may extend into theanterior chamber to a depth that would not damage the endothelial cells.For example, in some variations, implants may only extend less thanabout 2 mm, less than about 1 mm, less than about 0.5 mm, less thanabout 0.25 mm, between about 2 mm and about 0.25 mm, between about 2 mmand about 0.5 mm, between about 2 mm and about 1 mm, between about 1 mmand about 0.25 mm, between about 1 mm and about 0.5 mm, or between about0.5 mm and about 0.25 mm into the anterior chamber.

Intraocular implants may also reside fully intramurally (e.g., embeddedor positioned entirely within a tissue or tissues of the eye), such as,for example, the cornea, sclera, limbus, or a combination thereof. Incertain variations, the implant body may reside fully within the cornea,such as, for example, with a first end and a second end residing in thecornea. In certain variations, the implant body may reside fully withinthe sclera, such as, for example, with a first end and a second endresiding in the sclera. In certain variations, the implant body mayreside partially within the limbus, with a first end residing in thecornea, a second end residing in the sclera, and a portion therebetweenresiding in the limbus. In certain variations, the implant body mayreside partially within the limbus, with a first end residing in thesclera, a second end residing in the cornea, and a portion therebetweenresiding in the limbus. In certain variations, the implant body mayreside fully intramurally, with a first end residing in the limbus and asecond end residing in the sclera. In certain variations, the implantbody may reside fully intramurally, with a first end residing in thesclera and a second end residing in the limbus. In certain variations,the implant body may reside fully intramurally, with a first endresiding in the limbus and a second end residing in the cornea. Incertain variations, the implant body may reside fully intramurally, witha first end residing in the cornea and a second end residing in thelimbus.

It may be beneficial for intraocular implants or implant bodies to haveone portion and/or end residing at least partially intramurally andanother portion and/or end to reside outside of the eye (e.g., in thesubconjunctival space). In some variations, an implant resides partiallyin the sclera and partially outside the eye (e.g., in thesubconjunctival space). In some variations, an implant resides partiallyin the limbus and partially outside the eye (e.g., in thesubconjunctival space).

It may also be beneficial for intraocular implants or implant bodiesresiding fully intramurally to interface with an interior structure ofthe eye. For instance, in some variations, an implant may be fullyembedded within the sclera such that a first end of the implant orimplant body penetrates the inner scleral wall but does not protrudeinto the anterior chamber. In some variations, an implant may beembedded at least partially in the limbus, partially in the limbus andpartially in the sclera, or partially in the limbus and partially in thecornea, without protruding into the anterior chamber, but may interfacewith an interior structure or cavity of the eye (e.g., anteriorchamber). In other words, one tissue (e.g., limbus) may interface withanother structure or cavity of the eye (e.g., anterior chamber, cornea,sclera). In some variations, an implant may be partially or fullyembedded within the limbus, such that a first end of the implant orimplant body penetrates the limbus but does not protrude into theanterior chamber. As described above, positioning an implant in thismanner may avoid damaging endothelial cells (e.g., corneal endothelialcells).

An intramural implant residing at least partially in the limbus mayreside 100% within the limbus. In some variations, an intramural implantresiding at least partially in the limbus may reside 1-10%, 10-20%,20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100%within the limbus. In some variations, an intramural implant may resideabout 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% within thelimbus. An intramural implant may also, for example, reside (by lengthof the implant body) approximately ⅓ in the cornea and ⅔ in the limbus,⅔ in the cornea and ⅓ in the limbus, ⅓ in the limbus and ⅔ in thesclera, ⅔ in the limbus and ⅓ in the sclera, or ⅓ in each of the cornea,limbus, and sclera. An implant may also reside ½ in the cornea and ½ inthe limbus, or ½ in the limbus and ½ in the sclera. In some variations,an implant resides about 10% in the limbus and 90% in the cornea and/orsclera; about 20% in the limbus and about 80% in the cornea and/orsclera; about 30% in the limbus and 70% in the cornea and/or sclera;about 40% in the limbus and about 60% in the cornea and/or sclera; about50% in the limbus and 50% in the cornea and/or sclera; about 60% in thelimbus and about 40% in the cornea and/or sclera; about 70% in thelimbus and 30% in the cornea and/or sclera; about 80% in the limbus andabout 20% in the cornea and/or sclera; or about 90% in the limbus and10% in the cornea and/or sclera. It should be understood that “X %within the cornea and/or sclera” encompasses any sub-combination therein(e.g., where X % is 60%, the corresponding values may be 30% in thesclera and 10% in the cornea, or any other combination adding up to40%).

Exemplary Intraocular Implants

Turning now to the figures, FIGS. 2A-2G depict variations of intraocularimplants comprising implant bodies and, in some variations, one or moreanchoring elements. FIGS. 2H-2J depict variations of intraocularimplants comprising implant bodies and a separate, drug-eluting housing.It should be appreciated that any of the intraocular implants depictedin FIGS. 2A-2J may comprise any of the anchoring elements describedherein, and may further comprise a drug-eluting housing, even if notdepicted in the variations shown in FIGS. 2A-2J.

FIGS. 2A-2E depict intraocular implants (200A-200E) comprising animplant body in the form of an elongate cylindrical member (202A-202E).Each of the elongate cylindrical members (202A-202E) may be tubular,such that each has a lumen or cavity therein, or each may be solid. Oneor more drugs may be contained within the elongate cylindrical member(202A-202E) (e.g., within a reservoir in the cavity or lumen of theelongate cylindrical member, within a drug-eluting matrix forming theelongate cylindrical member) and/or all or a portion of the elongatecylindrical member (202A-202E) may be coated with a drug-eluting matrixcontaining one or more drugs. FIG. 2F depicts an intraocular implant(200F) comprising an implant body (202F) in the form of a coil and FIG.2G depicts an intraocular implant (200G) comprising an implant body(202G) in the form of a filament.

As described herein, the intraocular implants may comprise one or moreanchoring elements, variations of which can be seen in FIGS. 2A, 2B, 2C,2D, 2E, and 2G. Starting with FIG. 2A, implant body (202A) may comprisea first anchoring element (204A) and a second anchoring element (206A).The first anchoring element (204A) may comprise one or more (e.g., two,three, four, or more) expandable arms at or near a first end of theimplant body (202A) and the second anchoring element (206A) may comprisea flat or curved head (e.g., with a circular shape) or crossbar at ornear a second end of the implant body (202A). In some variations, theintraocular implant (202A) may have a configuration similar to adry-wall screw or anchor (tubular body with expandable arms and head).In this variation, in use, the head or crossbar may be positioned on afirst side of tissue (e.g., sclera) and the expandable arms may bepositioned on a second, opposite side of the tissue (e.g., sclera). Inother variations, the head or crossbar may be sunken into the tissue,such that a top surface of the head or crossbar is aligned with thesurface of the tissue.

Moving to FIG. 2B, the implant body (202B) of the intraocular implant(200B) may comprise a first anchoring element (204B) and a secondanchoring element (206B). The first anchoring element (204B) maycomprise threads or a coil positioned along all or a portion of thelength of implant body, and the second anchoring element (206B) maycomprise a flat or curved head (e.g., with a circular shape) or crossbarat or near a second end of the implant body (202B). In some variations,the implant body (202B) may be tubular, and the threads or coil may bepositioned within tissue (e.g., within the sclera), and the head orcrossbar may be positioned on a first side of tissue (e.g., sclera). Inother variations, the head or crossbar may be sunken into the tissue,such that a top surface of the head or crossbar is aligned with thesurface of the tissue.

As depicted in FIG. 2C, the implant body (202C) of the intraocularimplant (200C) may comprise one or more (e.g., two, three, four, ormore) anchoring elements (204C) along the length of the implant body(202C). The anchoring elements (204C) may comprise crossbars or barbs.The crossbars or barbs may be positioned within a tissue (e.g., sclera),on a first side of a tissue (e.g., sclera), on a second, opposite sideof the tissue (not depicted) or a combination thereof. In somevariations, the crossbars or barbs may be positioned on a first side ofa tissue and within a tissue.

As depicted in FIG. 2D, the implant body (202D) of the intraocularimplant (200D) may comprise one or more (e.g., two, three, four, ormore) anchoring elements (204D) along the length of the implant body(202D) and the anchoring elements (204D) may comprise beads. The beadsmay be positioned within a tissue (e.g., sclera), on a first side of thetissue (e.g., sclera), and/or on a second, opposite side of the tissue(e.g., sclera). In some variations, the beads may be positioned on afirst side of a tissue on a second, opposite side of a tissue, andwithin the tissue, as depicted in FIG. 2G. The intraocular implant(202D) may further comprise a housing (208) coupled to the implant body(202D) carrying one or more drugs, as described in detail herein. Insome variations, the implant body may reside partially in the sulcus,partially in the sclera, and partially in the subconjunctival space, andthe housing (208D) may be attached to a first end of the implant body.In this variation, the housing (208D) may be positioned in the sulcus.

As depicted in FIG. 2E, the implant body (202E) of the intraocularimplant (200E) may be positioned in a tissue (e.g., sclera) at an acuteor obtuse angle. The implant body (202E) may comprise one or more (e.g.,two, three, four, or more) anchoring elements (204E) along the length ofthe implant bodies (202E). The anchoring elements (204E) may comprisecrossbars or barbs. In use, the crossbars or barbs may be positionedwithin a tissue (e.g., sclera), on a first side of the tissue (e.g.,sclera), and/or on a second side of the tissue. In some variations, thecrossbars or barbs are positioned on a first side of the tissue andwithin the tissue. The implant body may be angled within a tissue toprevent the implant body from moving within or out of the tissue.

As depicted in FIG. 2F, the implant body (202F) of the intraocularimplant (200F) may comprise a coil. The coil may comprise a lumen orcavity partially or fully therethrough, or may be solid. In variationscomprising a lumen or cavity (e.g., may be hollow), one or more drugsmay be contained within the lumen or cavity of the coil and/or all or aportion of a coil may be coated with a drug-eluting matrix containingone or more drugs. The coiled implant body (202F) may be positionedwithin a tissue (e.g., sclera). In some variations, a first end of thecoiled implant body (202F) may be positioned on a first side of a tissue(e.g, sclera), and a second end of the coiled implant body (202F) may bepositioned on a second side of the tissue. In some variations, a firstend of the coiled implant body (202F) may be positioned on a first sideof a tissue (e.g., sclera), and a second end of the coiled implant body(202F) may be positioned within the tissue.

FIG. 2G depicts an intraocular implant (200G) comprising an implant body(202G) in the form of a filament or suture. In some variations, all or aportion of the implant body (202G) may be coated with or may comprise adrug-eluting matrix containing one or more drugs. In some variations,the intraocular implant (200G) may comprise one or more anchoringelements (204G) (e.g., a bead, a knot). The anchoring elements may bepositioned anywhere along the length of the implant body and in somevariations, such as those comprising knot anchoring elements, the knotsmay be formed from the implant body itself (e.g., may be knots formed inthe suture or filament at one or more locations along its length). Inuse, the anchoring elements may be positioned along a length of theimplant body (202G) between a first end of the implant body and thesclera, along a length of the implant body (202G) within the sclera,along a length of the implant body (202G) between the sclera and asecond end of the implant body (202G), or any combination thereof.

FIGS. 2H-2J depict intraocular implants (200H-200J) comprising implantbodies in the form of filaments or sutures. The intraocular implants(200H-200J) each further comprise a housing (208H-208J) coupled to theimplant body (202H-202J). One or more drugs may be contained within thehousings (208H-208J) coupled to the implant bodies (202H-202J) (e.g.,within a reservoir in the housing, within a drug-eluting matrix withinthe housing). In some variations, all or a portion of the housings(208H-208J) may be coated with a drug-eluting matrix containing one ormore drugs. FIG. 2H depicts an intraocular implant (200H) with theimplant body (202H) residing partially in the sulcus, partially in thesclera, and partially in the subconjunctival space. The housing (208H)is attached to a first end of the implant body (202H) such that thelongitudinal axes of the housing (208H) and the implant body (202H) areparallel. FIG. 2I depicts an intraocular implant (200I) with the implantresiding partially in the sulcus, partially in the sclera, and partiallyin the subconjunctival space. The housing (208I) is attached to a firstend of the implant body (202I) such that the longitudinal axis of thehousing (208) is transverse (e.g., perpendicular) to the longitudinalaxis of the implant body (202I). FIG. 2J depicts an intraocular implant(202J) with the second end of the implant body (202J) residing entirelyin the sclera and a first end of the implant body (202J) residing in thesulcus. The housing (208J) is attached to a first end of the implantbody (202J) such that the longitudinal axis of the housing (208J) istransverse to the longitudinal axis of the implant body (202J). In somevariations, the intraocular implants (202H-202J) may comprise one ormore anchoring elements (e.g., a bead, a knot). The anchoring elementsmay be positioned anywhere along the implant body, including, when inuse, along a length of the implant body (202H-202J) between the housing(208H-208J) and the sclera, along a length of the implant body(202H-202J) within the sclera, along a length of the implant body(202H-202J) between the sclera and a second end of the implant body(202H-202J), or any combination thereof.

FIG. 3A depicts an intraocular implant (300A) comprising an implant body(302A), a first anchoring element (304A) and a second anchoring element(306A). The first and second anchoring elements (304A, 306A) eachcomprise a knot or bead positioned at or near each end of the implantbody (302A). In some instances, the first anchoring element (304A)(e.g., the anchoring element positioned at or near the first end of theimplant body) may be erodible, while the implant body (302A, 302B, 302C)and second anchoring element (306A) may be non-erodible. FIG. 3B depictsan intraocular implant (300B) comprising an implant body (302B), a firstanchoring element (304B), and a housing (308B). The first anchoringelement (304B) comprises a knot or bead positioned at or near the secondend of the implant body (302B). The housing (308B) is positioned at ornear the first end of the implant body (302B). FIG. 3C depicts anintraocular implant (300C) comprising an implant body (302C), a firstanchoring element (304C), and a housing (308C). The first anchoringelement (304C) comprises a crossbar (which may be formed from, e.g., asuture or a filament) positioned at or near the second end of theimplant body (302C). The housing (308C) is positioned at or near thefirst end of the implant body (302C). In FIGS. 3A, 3B, and 3C, theanchoring element (304A, 304B, 304C) is positioned in thesubconjunctival space (knot or bead, and filament, respectively), and ahousing (308B or 308C), which may, in this variation, also serve toanchor the intraocular implant in addition to deliver drug, ispositioned in the sulcus.

FIG. 3D shows another variation of an intraocular implant. As shownthere, the intraocular implant (300D) may comprise an elongate implantbody (302D) comprising a lumen (310D) at partially therethrough, astopper (312D), a cavity (314D) containing a drug, a solution of a drug,a slurry of the drug, an emulsion of the drug, or a drug-eluting matrix,a first end (316D) and a second end (318D). The cavity (314D) may bepositioned at or near the first end (316D) of the implant body (302D)and the first end (316D) may be fully or partially open to allowdelivery of the drug in the cavity to the eye. The second end (318D) mayalso be fully or partially open to allow passage of a delivery device(e.g., a guidewire) into the lumen (310D) of the elongate implant body(302D).

A stopper (312D) may be positioned between the lumen (310D) and thecavity (316D) containing the drug, and may be configured to assist indelivery of the implant using the delivery device. For example, in somevariations, the stopper (312D) may be solid. The stopper (312D) may beformed integrally with the elongate implant body (302D), or may beformed separately and positioned within the lumen (312D) of the implantbody (302D) to form an end of the lumen (320D). In some variations, thestopper (312D) may directly separate the lumen (310D) and the cavity(314D). In some variations, the elongate implant body (302D) maycomprise a single lumen entirely therethrough, which may be formed intothe lumen (310D) and the cavity (314D) by placement of the stopper(312D) within the single, through body lumen. Thus, in some variations,the diameters of the lumen (310D) and the cavity (316D) may be the same.In other variations, the diameter of the lumen (310D) may be larger thanor smaller than the diameter of the cavity (316D). The solid stopper(1312D) between the first and second hollow ends of the elongate implantbody allows for contact with a delivery device or a portion of adelivery device. In some embodiments, a guidewire or pusher makescontact with the stopper during advancement and/or positioning of theimplant within the eye. In some variations, the elongate implant body(302D) may comprise polymer (e.g., nylon or polypropylene) and/or may bein the form of a filament or suture.

The intraocular implant (300D) may further comprise anchoring elements(304D and 306D). The anchor elements (304D and 306D) may be positionedon either side of the stopper (e.g., proximal to and distal to thestopper). In some variations, one or more anchoring elements (304D and306D) may be aligned with the cavity (314D) containing the drug (e.g.,the anchoring element may be positioned along the implant body (302D) ata location in which the implant body (302D) contains drug therein). Insome variations, the anchoring elements (304D and 306D) may compriseexpandable arms, which may serve as crossbar anchoring elements. Theexpandable arms may be configured such that they expand during or afterimplantation of the elongate implant body, and may be configured toprevent the elongate implant body from significantly moving relative to(e.g., back through) the sclera.

FIGS. 4A-4E show exemplary variations of intraocular implants(400A-400E) comprising implant bodies (402A, 402B, 402C, 402D, 402E)with housings (408A, 408B, 408C, 408D, 408E) comprising a drug coupledto an end thereof. FIG. 4A shows a housing (408A) comprising a reservoircontaining a drug. FIG. 4B shows a housing (408B) comprisingfenestrations in a sidewall thereof for controlled release of a drugcontained therein. FIG. 4C shows a housing (408C) in the form of a cage.The cage contains a reservoir comprising the drug. FIG. 4D shows ahousing (408D) with an internal surface coated with or containing adrug. FIG. 4E shows a housing (408E) with an external surface coatedwith a drug.

As described in more detail herein, the intraocular implant devices maycomprise a reservoir containing a drug. The reservoir containing thedrug may be attached directly to the implant body, may be positionedwithin the implant body, or may be positioned within a housing coupledto the implant body. Reservoirs can take many forms, including but notlimited to, blisters, balloons, or cylinders, which may themselves beremovable and replaceable. In some embodiments, a reservoir may compriseone or more delivery ports through which a drug may be injected. Thus,the intraocular implants described herein may be refillable. Exemplaryreservoirs (522A, 522B, 522C, 522D, and 522E) suitable for use in orwith the disclosed implants are highlighted in FIGS. 5A-5E. FIG. 5Adepicts a blister or balloon reservoir (522A) configured to receive adrug injected directly therein. In some variations, the reservoir may berefilled once or multiple times, e.g., by multiple injections. FIG. 5Bdepicts a blister or balloon reservoir (522B) with a port (524B), flushwith the surface of the reservoir, for receiving a drug within thereservoir (522B) by injection or similar means. FIG. 5C depicts areservoir (522C) with a port (524C) extending from the surface of thereservoir that can dock with a refilling needle. FIGS. 5D and 5E showcylindrical reservoirs (522D, 522E).

Exemplary Implant Locations

As discussed in detail herein, the intraocular implants may beconfigured to be advanced into the eye and positioned to deliver drug tovarious portions of the eye. For example, in some variations, theintraocular implants may be configured to be positioned at leastpartially in a tissue of the eye. In some instances, the intraocularimplant may be positioned at least partially within the sclera (104).FIGS. 6-11 depict exemplary locations for the intraocular implantsdescribed herein within the eye. FIG. 9 depicts an intraocular implant(900) comprising an implant body configured to be advanced into the eyethrough the sclera and positioned such that the second end of theimplant body is positioned entirely within the sclera.

In certain embodiments, the intraocular implants may be positionedwithin the eye such that one end of the implant (e.g., anon-drug-eluting end) is outside of the sclera, while the other end ofthe implant (e.g., a drug-eluting end) is positioned within the sulcus.FIGS. 2A-2J depict intraocular implants with implant bodies (202A-202J)positioned at least partially in the sclera. In some embodiments, thesecond end of the implant body may be configured to be positioned in thesubconjunctival space.

In some embodiments, an intraocular implant may comprise an implantbody, where the first end of the implant body is positioned in thesulcus or anterior chamber and the second end of the implant body ispositioned in the subconjunctival space. This is depicted in FIG. 6 . Incertain embodiments, an intraocular implant may comprise an implantbody, where the first end of the implant body comprises a drug-elutingreservoir or housing and may be positioned in the sulcus, and where thesecond end of the implant body may be positioned in the subconjunctivalspace. An example of this is depicted in FIG. 7 , which shows an implantbody (702) traversing the sclera, where the drug-eluting reservoir orhousing (708) is positioned within the sulcus of the posterior chamber.FIG. 16 depicts an implant body (1602) traversing the cornea, where thedrug-eluting reservoir or housing (1608) is positioned within theanterior chamber.

In some embodiments, an intraocular implant may comprise an implantbody, where the first end of the implant body is positioned in thevitreous and the second end of the implant body is positioned in thesubconjunctival space. In certain embodiments, an intraocular implantmay comprise an implant body, where the first end of the implant bodycomprises a drug-eluting reservoir or housing and may be positioned inthe vitreous, and where the second end of the implant body may bepositioned in the subconjunctival space. This is depicted in FIG. 17 ,where the implant body (1702) transverses the sclera, and thedrug-eluting reservoir or housing (1708) is positioned within thevitreous.

In some embodiments, an intraocular implant may comprise an implantbody, where the first end of the implant body is positioned in Berger'sspace or the Canal of Petit, and the second end of the implant body ispositioned in the subconjunctival space. FIG. 18 depicts an implant body(1802) traversing the sclera, where the first end of the implant body(1802) resides in Berger's Space. FIG. 19 depicts an implant body (1902)traversing the sclera, where the first end of the implant body (1902)resides in the Canal of Petit.

In certain embodiments, an intraocular implant may comprise an implantbody, where the first end of the implant body comprises a coil and ispositioned in the sulcus, and where the second end of the implant bodyis positioned in the subconjunctival space. An example of this isdepicted in FIG. 8 , which shows an implant body (802) traversing thesclera, where the first end of the coiled implant body is positioned inthe sulcus). In some embodiments, an intraocular implant may comprise animplant body, where the first end of the implant body is positioned inthe sulcus and the second end of the implant body is positioned entirelyin the sclera. FIG. 9 depicts an implant body (900) positioned in thesclera and the sulcus, with the second end of the implant body (900)residing inside the sclera and the first end of the implant body (900)residing in the sulcus.

Also described herein are intraocular implants that are configured to bepositioned intramurally in one or more of the sclera, the cornea, andthe limbus. In certain variations, the implant body may reside fullywithin the cornea, with a first end and a second end residing in thecornea. In certain variations, the implant body may reside partiallywithin the limbus, with a first end residing in the cornea and a secondend residing in the sclera. In certain variations, the implant body mayreside partially within the limbus, with a first end residing in thesclera and a second end residing in the cornea. These arrangements aredepicted in FIG. 10 , where a first implant body (1000A) is positionedentirely in the cornea and a second implant body (1000B) is positionedpartially in the limbus, with one end residing in the cornea and one endresiding in the sclera.

Also described herein are intraocular implants that are configured to bepositioned partially or fully within the suprachoroidal space. FIG. 21depicts an intraocular implant comprising an implant body (2102), wherethe intraocular implant resides fully in the suprachoroidal space. FIG.22 depicts an intraocular implant comprising an implant body (2202)positioned partially in the suprachoroidal space and partially in theanterior chamber. In particular, one end of the implant body (2202)resides in the suprachoroidal space and the other end resides in theanterior chamber.

In certain variations, the implant body may reside fully intramurally,with a first end residing in the limbus and a second end residing in thesclera. In certain variations, the implant body may reside fullyintramurally, with a first end residing in the sclera and a second endresiding in the limbus. Such configurations are depicted in FIG. 11 ,which depicts a first implant body (1100A) residing partially in thesclera and partially in the limbus. In certain variations, the implantbody may reside fully intramurally, with a first end residing in thelimbus and a second end residing in the cornea. In certain variations,the implant body may reside fully intramurally, with a first endresiding in the cornea and a second end residing in the limbus. Suchconfigurations are also depicted in FIG. 11 , which also depicts asecond implant body (1100B) residing partially in the cornea andpartially in the limbus. In some variations, the implant body may bespherical, spheroid, or ovoid and may reside intramurally, such as fullyin the sclera. FIG. 20 depicts an intraocular implant comprising aspherical implant body (2002), where the intraocular implant residesfully in the sclera.

Intraocular implants of this type may release the drug directly into theintramural tissue (e.g., a wall of tissue in the eye), where it willdiffuse through the intramural tissue to ultimately reach the site ofdisease. In some cases, the drug diffuses into the uvea, retina,anterior chamber or the posterior chamber. For example, an intramuralimplant may elute or otherwise deliver a drug (e.g., bimatoprost,latanoprost) into the tissue of the eye, and the drug may dissolve bydiffusion into the anterior segment of the eye or uveoscleral tissue,where it may act to reduce a symptom of a condition of the eye or treata condition of the eye (e.g., lower intraocular pressure). In anotherexample, an intramural implant may elute or otherwise delivery a drug(e.g., dexamethasone) into the tissue of the eye and the drug maydiffuse into intraocular spaces (e.g., posterior chamber). In thisexample, at least some of the drug may ultimately reach the retina,where it may act to reduce a symptom of a condition of the eye or treata condition of the eye (e.g., reduce macular edema in diabetes or aftervein occlusion). In some cases, the intramural implants may be wellsuited to deliver low-molecular weight drugs (e.g., prostaglandins),which may diffuse quickly through the intramural tissue (e.g., sclera)to a target location in the eye (e.g., anterior or posterior chamber).Higher-molecular weight (e.g., 10 kDa to 200 kDa, or 10 kDa to 500 kDa)drugs (proteins, antibodies) may also diffuse through a mural tissue,although at a lower rate. Administration of higher-molecular weightdrugs via the implants described herein to an intramural tissue mayresult in diffusion to the anterior or posterior chamber. In somevariations, an implant (e.g., and intramural implant) may elute drug tothe ocular surface (e.g., subconjunctival space, or exterior surface ofthe eye).

For intramural implantation, the implant body can take a number offorms. For instance, the implant body may comprise a sphere, spheroid,ovoid, rod, filament, or capsule, any of which, may, in some variations,comprise an interior chamber. In some variations, the implant body maycomprise a sheet.

It should be appreciated that any of the intraocular implants describedherein may be positioned in any of the anatomical locations/positionsdescribed herein.

Delivery Devices

Also described herein are delivery devices configured to house theintraocular implants during advancement and to position the intraocularimplants at the desired location within the eye of a subject. Thedelivery devices described herein may be single-handed, single-operatorcontrolled devices such that a user may deliver the intraocular implantsdescribed herein without assistance. A delivery device described hereinmay deliver a drug (e.g., as a solid, liquid, emulsion) directly into atissue of the eye, alternatively or in addition to an implant.

FIG. 12 is a cross-sectional view of an exemplary ocular delivery devicewith an intraocular implant positioned therein. As shown there, thedelivery device (1200) may comprise a cannula (1202) coupled to a handle(1204). The delivery device (1200) may further comprise a tissue stop(1206) coupled to the handle (1204) and slideably coupled to the cannula(1202). In some variations, the tissue stop (1206) may be positionedaround the cannula (1202). For example, the tissue stop (1206) maycomprise a tube with a lumen therethrough, and the cannula (1202) may beslideably positioned within the lumen of the tissue stop or housing(1206). The handle (1204) may comprise a pusher or push rod (1210), anactuator (1212) (e.g., a slider, a button, a knob, or the like) for thepush rod, a spring (1216), a spring stop (1208) and a spring actuator(1214). The spring (1216) may be coupled between the spring stop (1208)and the tissue stop (1206). The handle (1204) may comprise a gripportion and a housing (1220) comprising a proximal end (1222) and adistal end (1224). In some variations, the grip portion may be raised,depressed, grooved, or otherwise textured in certain areas, which mayassist a user in holding the handle during an implantation procedureand/or may improve user comfort. The cannula may be slideably coupled toand may extend from, the distal end (1224) of the housing (1220). Thetissue stop (1206), which may be configured to assist a user in properlypositioning the intraocular implant and in controlling penetration depthof the implant, may also be coupled to the housing (1220), and may allowthe cannula (1202) to slideably move within the housing (1220). Asmentioned above, the delivery device (1200) may comprise a push rodactuator (1212), which may be fixedly coupled to the push rod (1210) toadvance the push rod (1210) relative to the cannula (1202) (and tissuestop (1206)) and release the implant (1218) from the delivery device(1200). The delivery device (1200) may also include a spring actuator(1214), which may be releasably coupled to the spring (1216) via thespring stop (1208), and releasably engaged with the push rod actuator(1212). The spring (1216) may initially be in a compressedconfiguration, and may be sandwiched between the spring stop (1208) andthe tissue stop (1206) or a portion of the handle housing (1220). Forexample, a first end of the spring may be fixedly coupled to the springstop (1208) and a second end of the spring may be fixedly coupled to thetissue stop (1206) (as depicted) or a portion of the handle housing(1220). When the push rod actuator (1212) is advanced or otherwisedeployed, a portion of the push rod actuator (1212) may contact aportion of the spring actuator (1214), which may release the spring(1216) from the compressed position, thereby retracting the spring stop(1208) and the cannula fixedly coupled thereto (1202). For example,prior to implantation, the spring actuator (1214) may be in an engagedposition, in which it constrains the movement of the spring (1216). Uponadvancement of the push rod (1210) via the push rod actuator (1212), afirst engagement feature (e.g., projection or protuberance) (1226) onthe push rod actuator (1212) may contact a second engagement feature(e.g., projection or protuberance) (1228) on the spring actuator (1214),which may push or otherwise displace the spring actuator (1214) from theengaged position to a disengaged position in which the spring actuator(1214) no longer constrains the position of the spring stop (1208). Whenthe spring actuator (1214) is moved from the engaged position to thedisengaged position, energy stored in the spring (1216) is released, andthe spring (1216) lengthens, pushing the spring stop (1208) and, thusthe cannula (1202) fixedly attached thereto, proximally (away from theimplant (1218)). In addition to disengaging the spring actuator (1214),advancement of the push rod actuator (1212) advances the push rod (1210)relative to the cannula (1202), thereby pushing the implant (1218)positioned within a lumen of the cannula (1202) out of the deliverydevice and delivering the implant (1218) to the eye. In this manner, thedelivery device (1220) may be configured to simultaneously orapproximately simultaneously deliver the implant (1218) and retract thecannula (1202) relative to the handle housing (1220). The deliverydevice may be configured for delayed delivery of the implant.

Accordingly, to deliver the implant to the eye, the delivery device(1200) with the implant (1218) preloaded therein may be advanced to adesired location within the eye with the cannula in an extended positionby advancing the handle housing (1220). The tissue stop (1206) may beplaced against tissue (e.g., sclera) at or near a target location, andthe actuator (1212) may be advanced or otherwise activated (e.g.,pressed, turned, etc.), thereby advancing the push rod (1210) anddisengaging the spring actuator (1214). Upon disengagement of the springactuator (1214), the spring (1216) may lengthen, retracting the cannula(1202) while the implant (1218) is delivered to the target location.After the energy in the spring (1216) has been released and the spring(1216) has lengthened, the cannula (1202) may be in a retractedposition. The delivery device (1200) may then be withdrawn from the eyewith the cannula in the retracted position, leaving the implant (1218)behind.

The cannula (1202) may be configured to provide easy and minimallytraumatic access to a mural tissue (i.e., the sclera, the limbus, thecornea), or to the sulcus via the sclera. Cannulas in the deliverydevices described herein may comprise distal tips that are blunt,sharpened, tapered, or beveled. In some variations, the cannula maycomprise a needle. In some variations, cannulas may comprise a cuttingsurface. The cannula may be made from any suitable material withsufficient stiffness to allow it to be advanced through the sclera oranother mural tissue. For example, the cannula may be formed of a metalsuch as stainless steel, nickel, titanium, aluminum, or alloys thereof,or a polymer.

The spring (1202) may be formed of a metal, such as stainless steel,nickel titanium, aluminum, or alloys thereof. Alternatively, it may beformed from a plastic or polymer with suitable rigidity and elasticity.The spring (1216) may be attached to the spring stop (1208) and tissuestop (1206) or handle housing (1220) by any suitable means, such as, forexample, by an adhesive, a fitting, welding, or the like.

The actuator (1212) may be configured to reversibly engage the springactuator (1214) in any manner suitable for controlled and predictablerelease of the energy in the compressed spring (1216). For instance, theactuator (1212) may comprise a ratchet system such that a portion of theactuator (1212) may advance in discrete steps until reaching the springactuator (1214), which may then be triggered. This configuration mayprovide a user with more control over the implantation procedure andgreater predictability as to when the implant (1218) may be releasedfrom the cannula (1202). As mentioned herein, the actuator (1212) maycomprise a slider, a knob, a button, or the like. The spring actuator(1214) may, for instance, comprise a cantilever arm. In some variations,the spring actuator (1214) may be configured to recompress the springfor implant removal.

Suitable markings, colorings, or indicators may be included on anyportion of the device to help identify the location or position of theend of the cannula, tissue stop, the push rod, the intraocular implant,or any other element of the delivery device.

In some variations, a guidewire and cannula system may be used todeliver the intraocular implants described herein. For instance, FIG. 13shows an exemplary intraocular implant delivery device (1300) comprisinga cannula (1306) and a guidewire (1308). An intraocular implant may bepositioned within the cannula (1306) and delivered to the eye using theguidewire (1308). For example, a hollow elongate implant body (1302) maybe preloaded or otherwise positioned within the cannula (1306). Theimplant may comprise a solid stopper (1312) between the first and secondhollow ends of the elongate implant body (1302). The solid stopper(1312) may provide a contact surface for the guidewire (1308), such thatafter advancement of the guidewire through the cannula (1306) andimplant body (1302), the guidewire may contact the stopper (1312) toadvance and/or position the implant. In this variation, the first end ofthe elongate implant body may comprise a lumen (1310), which may house adrug, a solution of a drug, or a drug-eluting matrix. The implant (1300)may additionally comprise collapsible anchoring elements (1304) that mayexpand upon insertion into the tissue and/or removal of the cannula(1306). It should be appreciated the cannula utilized in this deliverydevice may have any of the features of any of the cannulas describedherein.

FIG. 14 depicts posterior (1402) and anterior (1404) views of avariation of a delivery device (1400) suitable for delivering anintraocular implant described herein. The delivery device (1400) maycomprise a cannula (1406) disposed within a handle (1408). The cannula(1406) may have a lumen (1408) running the length of the needle,configured for an intraocular implant to be delivered therethrough. Thecannula (1406) may have a sharpened distal tip (1410). The cannula(1406) may have a longitudinal slot (1412) to facilitate positioning ofan implant with a cap or anchoring element. The cannula (1406) may bemade from any suitable material with sufficient stiffness to allow it tobe advanced through the sclera or another mural tissue. For example, thecannula may be formed of a metal such as stainless steel, nickel,titanium, aluminum, or alloys thereof, or a polymer.

The human sclera ranges from approximately 0.4 mm to approximately 1 mmthick in various places, and the limbus is approximately 1.5 mm toapproximately 2 mm thick. The delivery devices described herein may beconfigured to deliver an intraocular implant within this depth range.For instance, a guidewire used for delivering an intraocular implantdescribed herein may be configured to deliver an intraocular implant toa depth of about 0.1 mm, about 0.2 mm, about 0.3 mm, about 0.4 mm, about0.5 mm, about 0.6 mm, about 0.7 mm, about 0.8 mm, about 0.9 mm, or about1.0 mm (including all values and sub-ranges therein) within anintramural tissue of the eye as measured from the external surface ofthe conjunctiva. The delivery devices described herein may push animplant in place to a specific tissue depth. A needle or cannula of adevice described herein, or a needle or cannula separate from thedevices described herein, may be used to create a scleral opening, andthe intraocular implant may be delivered by a delivery device or system.Alternatively, a channeling instrument, similar to a corneal separatorfor intracorneal rings, or a femtosecond laser, may be used to create orprepare a tunnel, channel, or cavity for subsequent device implantation.

Further, as described above, and in the methods below, it may bebeneficial to deliver an implant fully intramurally in the eye with atleast a portion of the implant residing in a limbus, or an implantpartially within a tissue and partially within a cavity of the eye.Precisely delivering the implant to a desired location is important inorder to specifically target a treat certain tissues or structures ofthe eye.

Delivering the implant may be accomplished by advancing the implant intothe eye using a delivery device described herein. The implant may bedisposed within a cannula (e.g., a needle), and for instance, may beoffset from the distal tip of a cannula so the operator of the deliverydevice knows the location of the implant within the eye during theimplantation procedure, for instance, while advancing a cannula of thedevice. The implant may then be released from the delivery device in theproper location.

Precise delivery of an implant may be accomplished by positioning theimplant (e.g., disposed within a delivery device) within the eye. Inorder to assist in such positioning, the delivery device or a portionthereof (e.g., a cannula) may be configured to visually indicate (e.g.,via markings or indicators as described above) to a user how far toadvance the delivery device to achieve a desired implant delivery depth(e.g., how far to advance the delivery device into the eye to achieve aparticular implant placement within the eye). Additionally oralternatively, the relative position of the implant in the deliverydevice, in combination with the markings, or other individualindicators, can be adjusted depending on a combination of the length ofthe implant and the desired final positioning of the implant (e.g.,fully in the limbus, partially in the limbus and partially in thesclera, partially in the limbus and partially in the cornea, etc.).

For example, in some variations, the implant may be positioned within acannula of a delivery device such that the implant is offset from adistal tip of the cannula by a predetermined amount. The predeterminedamount may correspond to the distance that the distal tip of the cannulais observed to advance into the anterior chamber during delivery. Forinstance, if the implant is disposed in a cannula 1.0 mm from the distaltip of the cannula, the operator of the delivery device may advance thedistal tip of the cannula 1.0 mm or less into the anterior chamber. Thecannula may be withdrawn to position the implant in the desiredlocation. When the cannula is withdrawn, the implant thereby resides ina target tissue or structure of the eye (e.g., fully intramurally anddoes not protrude into the anterior chamber). In variations of thedevices described herein, withdrawing the cannula comprises activatingan actuator. In some variations, the actuator is coupled to the handleof a delivery device. Additionally or alternatively, the whole deliverydevice may be withdrawn without actuation of any additional component(e.g., a cannula with a guidewire is removed from the tissue of the eyein one motion). It should be appreciated that in some variations, thedelivery device, or a portion thereof, does not extend into the anteriorchamber of an eye.

Accordingly, the drug-eluting implant may be positioned for implantationwithin the delivery device at a desired distance from a distal tip of acannula, depending on the length of the implant and/or the desiredintramural location. For example, the implant may be disposed within acannula at a distance from the distal tip of the cannula sufficient toallow implantation in the intramural tissue or tissues withoutprotruding into the anterior chamber. In some variations of the devicesand methods described herein, the implant (e.g., as measured by one endof an elongate implant body, or the central point of a sphere orspheroid) is disposed about 0.1 mm to 1 mm, about 0.2 mm to about 1 mm,about 0.3 mm to about 1 mm, about 0.4 mm to about 1 mm, about 0.5 mm toabout 1 mm, about 0.6 mm to about 1 mm, about 0.7 mm to about 1 mm,about 0.8 mm to about 1 mm, about 0.9 mm to about 1 mm, about 0.1 mm to0.9 mm, about 0.2 mm to about 0.9 mm, about 0.3 mm to about 0.9 mm,about 0.4 mm to about 0.9 mm, about 0.5 mm to about 0.9 mm, about 0.6 mmto about 0.9 mm, about 0.7 mm to about 0.9 mm, about 0.8 mm to about 0.9mm, about 0.1 mm to 0.8 mm, about 0.2 mm to about 0.8 mm, about 0.3 mmto about 0.8 mm, about 0.4 mm to about 0.8 mm, about 0.5 mm to about 0.8mm, about 0.6 mm to about 0.8 mm, about 0.7 mm to about 0.8 mm, about0.1 mm to 0.7 mm, about 0.2 mm to about 0.7 mm, about 0.3 mm to about0.7 mm, about 0.4 mm to about 0.7 mm, about 0.5 mm to about 0.7 mm,about 0.6 mm to about 0.7 mm, about 0.1 mm to 0.6 mm, about 0.2 mm toabout 0.6 mm, about 0.3 mm to about 0.6 mm, about 0.4 mm to about 0.6mm, about 0.5 mm to about 0.6 mm, about 0.1 mm to 0.5 mm, about 0.2 mmto about 0.5 mm, about 0.3 mm to about 0.5 mm, about 0.4 mm to about 0.5mm, about 0.1 mm to 0.4 mm, about 0.2 mm to about 0.4 mm, about 0.3 mmto about 0.4 mm, about 0.1 mm to 0.3 mm, about 0.2 mm to about 0.3 mm,or about 0.1 mm to 0.2 mm from the distal tip of the cannula (includingall subranges and values therein). In some variations, the implant isdisposed about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0 orgreater mm from the distal tip of a cannula.

The delivery device may also be configured to directly interface withone or more tissues of the eye. For instance, the delivery device may bepositioned such that it is applied to, and/or rests on, a surface (e.g.,conjunctiva, sclera, cornea) of the eye near (e.g., above, superior to)the desired final implant location (e.g., intramural implant location).For example, a distal end of a cannula of a delivery device may be incontact with a tissue surface of the eye. In some embodiments, thedelivery device may be positioned perpendicularly to a surface of theeye. In some variations, the delivery device may be angled relative tothe surface of the eye (e.g., about 5, 10, 15, 20, 25, 30, 35, 40, 45,50, 55, 60, 65, 70, 75, 80, or 85 degrees relative to the surface of theeye).

Methods of Treating Conditions of the Eye

Methods of treating a condition in the eye of a subject using theintraocular implants described herein are also provided. In general, themethods described herein may comprise advancing a drug-eluting implantthrough the conjunctiva and the sclera of the eye of the subject,positioning a portion of the implant in the sclera and a first end ofthe implant in the sulcus, and delivering a drug from the implant to thesulcus of the subject to reduce a symptom of the condition of the eye.Methods described herein may comprise advancing a drug-eluting implantthrough the conjunctiva and/or the sclera of the eye, positioning adrug-eluting implant fully intramurally in the eye with at least aportion of the drug-eluting implant in a limbus of the eye, anddelivering a drug from the implant to an anterior chamber of the eye toreduce a symptom of the condition of the eye. Methods may also generallycomprise advancing a drug-eluting implant through the conjunctiva andthe cornea of the eye, positioning a portion of the implant in thecornea and a first end of the implant in the anterior chamber, anddelivering a drug from the implant to the anterior chamber to treat thecondition of the eye and/or to reduce one or more symptoms of thecondition of the eye. Any of the above-described intraocular implantsand delivery devices are suitable for use with the methods describedherein. A delivery device described herein may deliver a drug (e.g., asa solid, liquid, emulsion) directly into a tissue of the eye,alternatively or in addition to an implant

Prior to administering the drug-eluting implant, the eye may beanesthetized, and one or more antiseptics may be applied to the eye toprepare it for the implantation procedure. Anesthesia may include one ora combination of the following types of anesthesia: topical,subconjunctival, sub-Tenon's, peribulbar, and retrobulbar. In someinstances, an eyelid speculum may be applied to expose the ocularsurface and prevent the eyelids from closing. In some instances, it maybe advantageous to dilate the pupil. The procedure may also be performedat a slit lamp with the patient seated upright, or it may be performedat a microscope with the patient supine. In some embodiments, theimplant may be advanced and/or positioned using loupes, a sit lamp, or asurgical microscope. The procedure may be done in an operating room,although, advantageously, the methods described herein are suitable forbeing performed at a doctor's office or in a minor procedure room. Themethods described herein may be performed with or without the use ofgonioscopy or microinvasive glaucoma surgery (MIGS)-type implantations.Instead, many of the methods described herein allow for injection into atissue of the eye, performed at a slit lamp or in an office-basedsetting by an ophthalmologist or optometrist. While these procedures maybe performed in an operating room, there are many advantages toperforming them in an office-based setting (e.g., cost savings,convenience for the patients, increased appointment availability and/oraccess).

In some variations, the intraocular implant must be advanced through thesclera or cornea to reach the desired or target location or positionwithin the eye. Advancing the implant through the sclera or cornea maycomprise advancing the implant through the sclera or cornea in adelivery device. The methods may comprise puncturing the sclera orcornea with a needle or cannula, such as a needle or cannula of adelivery device, and advancing the needle or cannula carrying theimplant therein to a desired location, such as directly within a muraltissue or partially within the sulcus. In some embodiments, methods maycomprise creating an intramural tunnel or channel separately from, andprior to, advancing the implant to the target location. In thesevariations, the tunnel or channel may be created with an instrument suchas a needle or a femtosecond laser. In other variations, the channel ortunnel may be created using the implant delivery device prior to, orduring, advancement of the intraocular implant to the desired location.In some embodiments, the intraocular implant may be positioned withinthe mural tissue directly, or within a tunnel or channel, and may alsocomprise operating an actuator of the delivery device to release theimplant from the delivery device. The actuator may comprise, forinstance, a button, a knob, or a slider. In some variations, one or moreactuator may be coupled to a handle of the delivery device.

The methods may comprise positioning the implant partially in the sclerawith a first end residing in the sulcus, vitreous, or anterior chamberand a second end residing in the subconjunctival space. In certainvariations, the methods may comprise positioning the implant partiallyin the sclera with a first end residing in the sulcus, vitreous, oranterior chamber (e.g., in the iridocorneal angle) and a second endresiding in the sclera. In some embodiments, the implant may be advancedto a target position in which a portion of the intraocular implant ispositioned at least partially in the sclera and the remainder of theimplant may be positioned within one or more of the sclera, cornea, andlimbus. For instance, the methods may comprise advancing the intraocularimplant such that one end is positioned in the sclera and the other endis positioned in the sulcus. The methods may comprise advancing theintraocular implant such that one end is positioned in the sclera,limbus, or cornea and the other end is positioned in the anteriorchamber (e.g., the iridocorneal angle). The methods may compriseadvancing the intraocular implant such that one end is positioned in thesulcus and the other end is positioned in the subconjunctival space.Both ab-externo and ab-interno approaches to these methods arecontemplated.

In some variations, a space may be created in the cornea, limbus, and/orsclera with a device suitable for creating a pocket, channel, flap, orinterlamellar space. Such spaces can be created, for instance, withcorneal separators, microkeratomes, and/or femtosecond lasers.Subsequently, the implant may be deployed with a second device or systeminto the preformed space.

The methods described herein comprise positioning a portion of theimplant in the sclera and a first end of the implant in the sulcus. Insome embodiments, the positioning step comprises operating an actuatorto release the implant from the delivery device or system. As describedherein, the actuator may comprise a button, a knob, and/or a slider. Theactuator may, for instance, control a pusher in contact with or coupledto the intraocular implant. In some embodiments, a guidewire may contacta portion of the implant, and the implant may be advanced from a cannulaand/or positioned using the guidewire. After delivering the implant tothe target tissue with the guidewire, the implant may be released fromthe guidewire and/or the guidewire may be withdrawn, leaving the implantin place.

Generally, the methods described herein provide a means of anchoring theintraocular implant within the eye. In certain embodiments, thepositioning step comprises fixing a position of the implant using ananchoring element. Any number of anchoring elements may be used with theintraocular implants and methods described herein. As discussed above,suitable anchoring elements may be present on any portion of theelongate implant body, including any portion of the intraocular implantor the elongate implant body residing within the sclera, within thesulcus (between the first end of the elongate implant body and thesclera), or within the subconjunctival space. Suitable anchoringelements include knots, beads, barbs, coils, or crossbars. In someembodiments, the first and second anchoring elements are expandableanchoring elements (e.g., expandable barbs, expandable crossbars). Inthese embodiments, positioning an implant within the eye may comprisetransition the anchoring elements from a first, low-profileconfiguration to a second expanded configuration. For example, theanchoring elements may be held in the compressed, low profileconfiguration when the implant is positioned within the delivery device(e.g., within a needle or cannula of the delivery device) and oncereleased from the delivery device, the anchoring elements, no longerconfined by needle or cannula, may self-expand

Once the intraocular implant is advanced into the and positioned in thedesired location, the anchoring elements may be positioned in a varietyof locations within the eye to secure the implant in place. Forinstance, in some methods, an anchoring element may be positionedbetween the first end of the implant and the sclera. In some variationsin which the implant is positioned with a first end in the sulcus and asecond end in the subconjunctival space, an anchoring element may bepositioned in the sulcus. In some variations in which the implant ispositioned with a first end in the sulcus and a second end in thesubconjunctival space, an anchoring element may be positioned in thesubconjunctival space. In some variations in which the implant ispositioned with a first end in the sulcus and a second end in thesubconjunctival space, an anchoring element may be positioned in thesulcus and in the subconjunctival space. In some variations in which theimplant is positioned with a first end in the sulcus and a second end inthe subconjunctival space, an anchoring element may be positioned in thesulcus, in the subconjunctival space, and in the sclera.

In some variations in which the implant is positioned with a first endin the sulcus and a second end in the sclera, an anchoring element maybe positioned on a length of the implant residing in the sulcus. In somevariations in which the implant is positioned with a first end in thesulcus and a second end in the sclera, an anchoring element may bepositioned on a length of the implant residing in the sclera. In somevariations in which the implant is positioned with a first end in thesulcus and a second end in the sclera, an anchoring element may bepositioned on a length of the implant residing in the sulcus and on alength of the implant residing in the sclera.

In order to minimize movement and/or reduce the likelihood that theimplant will slide, migrate or otherwise move from the desired location(e.g., anteriorly or posteriorly), in some embodiments, the methodsdescribed herein may comprise fixing a position of the implant using aplurality of anchoring elements, such as a first anchoring element and asecond anchoring element. In some embodiments, the first anchoringelement may be positioned between the first end of the implant and thesclera, and the second anchoring element may be positioned in thesubconjunctival space. In some variations in which the implant ispositioned with a first end in the sulcus and a second end in thesubconjunctival space, the first anchoring element is present on alength of the implant residing in the sulcus and the second anchoringelement is present on a length of the implant residing in thesubconjunctival space. In some embodiments of the methods describedherein, at least one of the first anchoring element and the secondanchoring element may be an expandable anchoring element. In someembodiments, the first anchoring element and the second anchoringelement are knots; and wherein the first anchoring element is implantedwithin the sulcus and the second anchoring element is implanted in thesubconjunctival space. In some embodiments, the anchoring element is aknot.

The methods described herein may also prevent or minimize (e.g.,relative to conventional implants) damage of corneal endothelial cells,as the implants described herein may be prevented from making physicalcontact with the endothelium. The methods described herein may, forinstance, further comprise anchoring the drug-eluting implant within theeye, (e.g., within the sulcus, in the anterior chamber but distant fromthe endothelium), thereby resulting in minimal endothelial cell loss(e.g., endothelial cell loss negligible compared to typical age-relateddecline in endothelial cells). The endothelial cell loss may be lessthan about 1%, less than about 1.5%, less than about 2%, less than about2.5%, or less than about 3%.

FIG. 15 depicts a method of advancing and positioning an intraocularimplant (1500) comprising expandable anchoring elements (shown collapsedin FIG. 13 ) within the eye. The distal end (1516) of a delivery device,such as, for example, a cannula (1506), containing the implant body(1502) may be inserted through the sclera and into the sulcus. A pusher(e.g., guidewire) (1508) may be advanced through a lumen (1514) of thecannula, before, during or after advancement of the cannula, and maypush the implant into the sulcus (105). In some variations, the implantbody (1502) may comprise a stopper (1518), and the pusher may advancethe implant via contact with the stopper (1508). After being releasedfrom the cannula lumen (1515), a first anchoring element may expand(1512) within the sulcus. In this configuration, the first anchoringelement (1512) may be positioned between the first end of the implant,which may also be within the sulcus, and the sclera. In some variations,the pusher (1508) may continue to be advanced to release the remainderof the implant (1500), and any remaining anchoring elements (1505), fromthe cannula (1506), at which point the cannula and pusher may bewithdrawn from the eye. In other variations, the implant may bepartially advanced from the cannula lumen using the pusher, and theimplant may be fully released from the cannula lumen upon retraction orwithdrawal of the cannula. In these variations, withdrawal of thecannula may release the remainder of the implant (e.g., the second endof the implant) and any remaining anchoring elements from the cannula.The cannula and the pusher may then be removed from the individually ortogether. The intraocular implant may be left in the eye and may beembedded partially in the subconjunctival space and partially in thesulcus, traversing the sclera. As the pusher is continued to be advancedrelative to the cannula, or as the cannula is withdrawn while the pusherremains stationary, the remaining collapsed anchoring element(s)expands, e.g., in the subconjunctival space, anchoring the device (e.g.,on both sides of the sclera). As depicted in FIG. 15 , the first end ofthe intraocular implant comprises a drug, which then elutes (e.g., overa predetermined period of time) into the sulcus.

The methods described herein are suitable for use with any of theintraocular implants described previously. In some embodiments, theimplant comprises a filament. In some embodiments, an implant comprisinga filament may further comprise anchor elements that are knots, whereinthe knots are implanted within the sulcus.

Also described herein are methods for treating a condition in an eye ofa subject using intramural implants. Such methods may comprise advancinga drug-eluting implant through one or more of the sclera, limbus, andcornea of the eye of the subject, positioning the implant entirelywithin one or more of the sclera, limbus, and cornea, and delivering adrug from the implant to a portion of the eye (e.g., anterior chamber)to reduce a symptom of the condition of the eye. The methods maycomprise positioning the implant fully within the cornea, such as, forexample, with a first end and a second end residing in the cornea. Incertain variations, the methods may comprise positioning the implantfully within the sclera, such as, for example, with a first end and asecond end residing in the sclera. In certain variations, the methodsmay comprise positioning the implant partially within the limbus, with afirst end residing in the cornea, a central portion residing in thelimbus, and a second end residing in the sclera. In certain variations,the methods may comprise positioning the implant partially within thelimbus, with a first end residing in the sclera, a central portionresiding in the limbus, and a second end residing in the cornea. Incertain variations, the methods may comprise positioning the implantfully intramurally, with a first end residing in the limbus and a secondend residing in the sclera. In certain variations, the methods maycomprise positioning the implant fully intramurally, with a first endresiding in the sclera and a second end residing in the limbus. Incertain variations, the methods may comprise positioning the implantfully intramurally, with a first end residing in the limbus and a secondend residing in the cornea. In certain variations, the methods maycomprise positioning the implant fully intramurally, with a first endresiding in the cornea and a second end residing in the limbus. In somevariations, the methods may comprise positioning one portion and/or endof an implant residing at least partially intramurally and anotherportion and/or end to reside outside of the eye (e.g., in thesubconjunctival space). In some variations, the methods may comprisepositioning one end partially in the sclera and one end partiallyoutside the eye (e.g., in the subconjunctival space). In somevariations, the implant is positioned partially in the limbus andpartially outside the eye (e.g., in the subconjunctival space).

These methods are suitable for use with any of the intraocular implantsdescribed above.

As described above, advancing the implant (e.g., drug-eluting implant)may involve advancing a portion of a delivery device through a sclera ofthe eye. The implant may be disposed within the delivery device. Forexample, the implant may be disposed within a cannula of the deliverydevice, and at least a distal end of the cannula may be advanced througha sclera of the eye. The methods described herein may also allow forpositioning a drug-eluting implant fully intramurally with at least aportion of the drug-eluting implant in a limbus of the eye. The methodsdescribed herein may also allow for delivering a drug from thedrug-eluting implant, after placement of the implant, to a target tissueor tissues of the eye (e.g., anterior chamber) to reduce a symptom ofthe condition of an eye. The target tissue or tissues may be one or moretissues in which the implant resides. The target tissue or tissues maynot be in contact with the implant.

Generally, some implants may be fully or partially intramural. Forinstance, the drug-eluting implant, comprising a drug, may be placed atleast partially within the limbus of an eye of a subject. Such implantsmay also be fully intramural, which, as discussed previously, has theadvantage of preventing damage to one or more tissues (e.g., cornealepithelial cells) as compared to implants that extend into, or fullyreside and free-float within, the anterior chamber.

In order to deliver the implant, the method may comprise advancing adistal tip of a cannula of a delivery device (such as any of thedelivery devices described herein) through one or more tissues,cavities, or structures of the eye (e.g., through a sclera and a limbusinto an anterior chamber).

After advancing the cannula, wherein the implant is disposed, thecannula may be visualized in a particular portion of the eye or at aparticular depth, informing where in the eye the implant will resideonce the cannula is retracted. Thus, methods may further comprisevisualizing the distal tip of the cannula within a particular tissue,cavity, or structure of the eye (e.g., the anterior chamber) prior toreleasing the implant from the delivery device. For instance, thecannula may be visualized within one or more tissues, cavities, orstructures of the eye, within which the implant will reside.Additionally, or alternatively, the cannula may be visualized within oneor more tissues, cavities, or structures of the eye adjacent to, orwithin the proximity of, the desired implant location.

Visualizing the cannula through the posterior portion of the eye mayassist a user in in properly positioning the implant within the eye, asdescribed above. Accordingly, methods may comprise confirming the distaltip of the cannula is positioned within a desired portion of the eye,such as, within the anterior chamber of the eye. Once the distal tip ofthe cannula has been advanced to a desired depth within the eye, methodsmay further comprise retracting the cannula and releasing thedrug-eluting implant in the target tissue (e.g., at least partially inthe limbus).

In some variations of the methods described herein, the distal tip ofthe cannula of a delivery device may enter the anterior chamber duringpositioning of the drug-eluting implant, and the cannula may be advancedinto the anterior chamber to a depth corresponding to the offset of theimplant from the distal tip of the cannula (e.g., about 0.5 mm to about10.0 mm) in order to position the implant as desired. For example, insome variations, the cannula may be advanced into the anterior chamberto a depth that results in delivery of the implant to the limbus (e.g.,so that the implant resides at least partially within the limbus afterimplantation/release from the delivery device). In some of thesevariations, the implant may not enter the anterior chamber at all,either during implantation when the distal tip of the cannula is in theanterior chamber, or after, when the implant is residing in the eye fordelivery of drug thereto.

After advancing the distal tip of the cannula, positioning adrug-eluting implant may comprise retracting or otherwise withdrawingthe cannula in relation to the tissue of the eye, leaving the implant inthe desired tissue. The cannula may be retracted via operation of one ormore actuators of the delivery device. For instance, the cannula may beretracted via operation of 1, 2, 3, or more actuators, and the actuatormay comprise one or more of a button, knob, and slider. In somevariations, the cannula may be retracted by movement of a handle coupledthereto. In some variations, the cannula may be retracted by moving theentire body of the cannula, which may comprise additional structuralfeatures such as a handle. In variations, the implant stays stationaryduring retraction of the cannula.

In some variations, the cannula or drug-eluting implant may bevisualized during advancement and/or positioning using loupes, a slitlamp, a surgical microscope, or any combination thereof.

Positioning may also comprise fixing a position of the drug-elutingimplant to a tissue of the eye using at least one anchoring element.Examples of anchoring elements include surface ridges, knobs, ribs,bulbs, and barbs fixed to the implant. Any anchoring elements describedherein may be configured in such a way that they are stowed orundeployed while residing in the cannula and subsequently deployed oncethe cannula is retracted. Put another way, methods described herein maycomprise expanding or otherwise deploying one or more anchoringelements, such as, for example, automatically upon removal of theimplant from the delivery device.

In some variations, such as those where an implant resides fullyintramurally, anchoring elements may be positioned and fixed to one ormore tissues of the eye. For instance, in some of the methods describedherein, at least one anchoring element may be positioned in and coupled(e.g., fixed) to the limbus. In some embodiments, at least one anchoringelement may be positioned in and coupled to the sclera. In certainembodiments, at least one anchoring element may be positioned in andcoupled to the cornea. A plurality of anchoring elements may bepositioned and coupled to more than one tissue, such as the limbus andsclera; the limbus and cornea; or the limbus, cornea, and sclera.Specifically, multiple anchoring elements may be coupled to the sametissue. In some variations in which there are multiple anchoringelements, each anchoring element may be coupled to a different tissue.

The implants described herein may deliver drugs to various locations,irrespective of where in the eye they reside. In any of the methodsdescribed herein, a drug-eluting implant may deliver a drug to a tissueor tissues in which the drug-eluting implant resides, and/or to alocation or tissue(s) that is different from the tissue or tissues inwhich the drug-eluting implant resides. For instance, a drug-elutingimplant may reside fully intramurally but may deliver a drug to theanterior chamber of the eye via diffusion through the tissue(s). Adrug-eluting implant residing fully in the limbus may deliver a drug toone or more of the limbus, sclera, cornea, anterior chamber, or anyother nearby tissue or structure of the eye. A drug-eluting implantresiding partially in the limbus and partially in the sclera may delivera drug to one or more of the limbus, sclera, cornea, anterior chamber,or any other tissue or structure of the eye. In certain variations, thedrug from the drug-eluting implant may diffuse through one or moreaqueous outflow channels. FIGS. 23A-23G depict an exemplary method ofplacing a drug-eluting implant at least partially within a limbus of aneye.

By way of example, the first step in placing a drug-eluting implant mayinvolve preparing the eye for the procedure. Specifically, FIG. 23Adepicts a eye pre-procedure, prior to placing a drug-eluting implant(2300A) at least partially within the limbus (2302A) of an eye. Forreference, and as described above, the limbus lies between the cornea(2304A) and the sclera (2306A). The implant (2300A) may be positionedwithin the delivery device such that the implant (2300A) is disposed inthe cannula (2310A) a pre-defined distance from the distal tip (2312A)of the cannula. The ocular surface (2314A) may be anesthetized, and/orantiseptic drops may be placed on the eye. An eyelid speculum may beinserted to keep the eyelids open for the duration of the procedure.

After preparing the eye, a cannula may be advanced toward the subject'socular surface. The cannula (2300B) of the delivery device (2302B)carrying the implant (2304B), as shown in FIG. 23B, may be advancedtoward the sclera (2306B) posterior to the limbus (2308B).

After orienting the cannula of a delivery device, the cannula carryingthe implant enters the eye at a location sufficient to reach the targettissue or structure of interest. As shown in FIG. 23C, the distal tip(2300C) may be advanced into the sclera (2306C) posterior to the limbus(2308C). In some variations, the distal tip (2300C) of the cannula(2302C) of the delivery device (2304C) may be advanced into the sclera(2306C) about 2-3 mm posterior to the limbus (2308C). As shown in FIG.23C, in some variations, the cannula may be advanced at an angle intothe sclera such that the distal tip (2300C) will pass through the sclera(2304), through the limbus (2308C), and into the anterior chamber(2310C).

The cannula is then advanced through one or more tissues or structuresof the eye toward the desired implant location. FIG. 23D depicts thedistal tip (2300D) of the cannula (2302D) of a delivery device (2304D),within which the implant (2306D) is disposed, advancing through thesclera (2308D) and limbus (2310D).

The proper positioning of the implant may be confirmed by visualizing acomponent of the delivery device (e.g., a cannula), externally, usingmethods described above. FIG. 23E depicts the distal tip (2300E) of thecannula (2302E) advancing into the anterior chamber (2304E) anterior tothe iris (2306E). For instance, the distal tip (2300E) may enter at theanterior chamber angle (2308E) or in the cornea (2310E) just anterior tothe anterior chamber angle (2312E). Advancement of the cannula (2302E)may be visualized (e.g., with a surgical or slit lamp). The depth towhich the distal tip (2300E) is advanced into the anterior chamber(2304E) may be predetermined based on the size of the implant (2314E)and the desired final intramural position of the implant (2314E). Forinstance, in variations in which a 0.5 mm implant is used, and isimplanted fully intramurally at least partially in the limbus, withoutentering the anterior chamber, the implant may initially be disposed inthe cannula 1 mm from the distal tip. The distal tip is visualized as itis advanced into the anterior chamber to a depth of 1 mm or less,meaning that the implant disposed 1 mm from the tip, is still fullyintramural and has not entered the anterior chamber. The cannula canthen be retracted, leaving the implant intramurally, at least partiallywithin the limbus.

Once the proper position of the implant is attained, the cannula isretracted. FIG. 23F depicts the retraction of the cannula (2300F), whichmay release the implant (2302F) from the cannula (2300F) and, in thisvariation, implant it intramurally, and at least partially within thelimbus (2304F). In some variations, the cannula (2300F) may be retractedvia operation of an actuator of the delivery device (2306F) (e.g., on ahandle of the delivery device). A portion or portions of the implant(2302F) may reside in the sclera (2308F) or the cornea (2310F),depending on the length of the implant (2302F). FIG. 24F shows theimplant (2300G) in its final location at least partially within thelimbus (2302G).

The methods of treating a condition in of an eye of a subject, asdescribed herein, may be useful for treating a number of oculardisorders or conditions. These ocular disorders include, but are notlimited to, glaucoma, AMD, choroidal diseases, retinal diseases, cornealdiseases, iris diseases, uveal diseases, lens diseases, and scleraldiseases (e.g., myopia). In some embodiments, the methods describedherein may be useful for treating macular edema, vascular occlusions,diabetic retinopathy, retinal degenerations, and retinal dystrophies,iritis, uveitis, vitritis, cataracts, herpes zoster or simplexinfection, keratitis, keratoconus or other corneal degenerations, dryeye disease, scleritis, episcleritis, corneal ulcer, astigmatism,hyperopia, presbyopia, cornea ectasia, corneal dystrophies, cornealscars, graft versus host disease, autoimmune ocular diseases, Thygeson'skeratitis, post-viral keratitis, herpes simplex, viral keratitises,uveitis, Stevens Johnson Disease, conjunctivitis, blepharitis,postoperative inflammation, postoperative infection prophylaxis,postoperative pain, pingueculum, pingueculitis, pterygium, vernal andatopic keratoconjunctivitis, allergic conjunctivitis, chemical injuries,thermal injuries, chemical injuries, mechanical injuries, retinalvasculitis, retinal dystrophies, neuroretinopathies, autoimmune retinaldiseases, autoimmune choroidal diseases, retinal detachment, retinaltears, retinal breaks, ischemic and nonischemic optic neuropathies,tapetoretinal dystrophies, ocular trauma, radiation retinopathy,exudative or nonexudative age related macular degeneration, choroidalneovascularization, retinal neovascularization, retinal vascularocclusive disease, choroidal or retinal inflammation, vitreous opacities(e.g., hemorrhage, floaters, asteroid hyalosis), maculopathies,retinopathies, choroidopathies, retinopathy of prematurity,endophthalmitis, epiretinal membrane hole, macular hole, proliferativevitreoretinopathies, edema (e.g., macular, retinal), ischemia (e.g.,macular, retinal), or diabetic retinopathy. In some variations, themethods described herein may result in decreased duration, severity,and/or occurrence of one or more symptoms of any of the aforementionedconditions and/or may result in treatment of any of the aforementionedconditions. The methods described herein, therefore, may utilize adrug-eluting implant that delivers a drug to treat any of these, orother, disorders or conditions. In some embodiments, the dug-elutingimplant may deliver a glaucoma drug. In some variations, the methodsdescribed herein may utilize a drug-eluting implant located partially ina first part of the eye to treat a disorder in the same part of the eyeor another part of the eye.

Because the methods of this disclosure provide for long-termadministration of a drug to eye tissue, in some variations, it may bedesirable to replace drug that has diffused from the drug-elutingimplant. Thus, some embodiments of the methods disclosed herein furthercomprise refilling the drug-eluting implant and/or replacing a drugreservoir coupled to or contained with the implant. Refilling thedrug-eluting implant may be accomplished, for instance, by delivering adrug, a solution of the drug, a slurry of the drug, and emulsion of thedrug, or a drug-eluting matrix by injection into one or more hollowcavities, lumens, or reservoirs in the drug-eluting implant within theeye. As described previously, some reservoirs comprise a port throughwhich drug can be provided. The methods described herein allow forrefilling the drug-eluting implant with the same or differenttherapeutic agent. In some variations, instead of refilling a drugreservoir, the reservoir may be removed and replaced with a newreservoir containing a drug, a solution of the drug, a slurry of thedrug, and emulsion of the drug, or a drug-eluting matrix.

The methods described herein also allow for removal of the implant fromthe eye after it has been implanted. For instance, the implant may beremoved from the eye once treatment has finished. In some variations, aninstrument configured for removal of an implant or implant body mayengage with a portion of the implant or implant body, such as, an end ofthe implant body, a central portion of the implant body, an anchoringelement, and/or a portion of a housing. In embodiments in which theimplant body comprises a suture or filament, an instrument may engage anend of the suture or filament for retrieval of the implant from the eye.In some variations of the methods described herein, implants mayadditionally comprise a removal feature configured to be grasped forremoval of the implant from the eye. For example, in some variations,the removal feature may comprise a wire, filament, suture, tab, or otherstructure coupled to the implant body or housing. In these variations,methods may comprise engaging the removal feature of the intraocularimplant with an instrument (e.g., forceps) and removing the implant fromthe eye using the removal feature. The implant may be removed after adrug-eluting matrix is absorbed or partially absorbed, decreasing thedimensions of an implant such that removal is easier. It may also bedesirable to remove the implant to refill the implant, replace thereservoir, or to replace the implant with a second or subsequent implantcomprising the same or a different therapeutic agent.

The methods described herein may comprise delivering a plurality (e.g.,two, three, four, or more) of implants to the eye. The implants may bedelivered such that they reside in the eye simultaneously and/orsequentially (e.g., the implants may both be implanted for the sameperiod of time, for different, overlapping periods of time, or fordifferent non-overlapping periods of time). In variations in which aplurality of implants are employed, the implants may comprise the samedrug, may comprise different drugs with the same mechanism of action forone or more conditions of the eye, or may comprise different drugs withdifferent mechanisms of action for one or more conditions of the eye.The implants may comprise a drug intended to treat or reduce a symptomof the same condition of the eye, or may comprise a drug intended totreat or reduce a symptom of different conditions of the eye. Moreover,the implants may be positioned in the same general location in the eyeor in different locations in the eye. It should be appreciated thatwhile the implants are described as comprising a drug, this may includecombinations of drugs.

For example, methods may comprise positioning a first implant comprisinga first drug intended to treat or reduce a symptom of a first conditionin a first location in the eye and positioning a second implantcomprising a second drug intended to treat or reduce a second conditionin a second location in the eye. In some variations, the first drug andthe second drug may be the same drug, the first condition and the secondcondition may be the same condition, the first implantation location andthe second implantation location may be the same location, and the firstdrug and the second drug may utilize the same mechanism of action. Inother variations, the first drug and the second drug may be differentdrugs, the first condition and the second condition may be differentconditions, the first implantation location and the second implantationlocation may be different locations, and/or the first and second drugsmay utilize different mechanisms of action. Thus, in some variations,the first and second drugs may be different drugs that utilize differentmechanisms of action, but the first and second locations may be the samelocation and the first and second conditions may be the same condition.In another example, the first and second drugs may be different drugsthat utilize different mechanisms of action and the first and secondlocations may be different locations, but the first and secondconditions of the eye may be the same. It should be appreciated that anycombination of drugs, mechanisms of action, locations, and conditions ofthe eye described herein may be used in combination when utilizingmethods comprising use of multiple intraocular implants.

For some subjects, it may be advantageous to deliver multiple implantsconfigured to deliver different drugs or to deliver drugs that utilizedifferent mechanisms of action as this may allow for a morecomprehensive treatment. For example, methods may comprise positioning afirst implant comprising a first drug with a first mechanism of actionwith a first end in the sulcus and positioning a second implantcomprising a second drug with a second mechanism of action at leastpartially in the anterior chamber or posterior chamber. In somevariations, the first mechanism of action may be suppression ofproduction of aqueous humor and the second mechanism of action may beincreasing the drainage of aqueous humor using one or more of thetrabeculocanicular pathway and the uveoscleral pathway. In othervariations, both the first mechanism of action and the second mechanismof action may be suppression of aqueous humor or increasing drainage ofaqueous humor using one or more of the trabeculocaniclular pathway andthe uveoscleral pathway. In some variations, the first and secondmechanisms of action may be increasing drainage of aqueous humor,however, the first mechanism of action may be increasing drainagethrough the trabeculocanicular pathway and the second mechanism ofaction may be increasing drainage through the uveoscleral pathway. Insome variations, the first implant may comprise a drug for treating orreducing one or more symptoms of glaucoma (e.g., by suppression ofaqueous humor, increasing drainage of aqueous humor using thetrabeculocanicular pathway, increasing drainage of aqueous humor usingthe uveoscleral pathway) or a condition of the retina, lens, cornea,uvea, vitreous, iris, ciliary body, sclera, or ocular surface, and thesecond implant may comprise a drug for treating or reducing one or moresymptoms of glaucoma or a condition of the retina, lens, cornea, uvea,vitreous, iris, ciliary body, sclera, or ocular surface. For example,the first implant and the second implant may each comprise a drug fortreating or reducing one or more symptoms of glaucoma, and the drug maybe the same or a different drug. In another example, the first implantmay comprise a drug for treating or reducing one or more symptoms ofglaucoma and the second implant may comprise a drug for treating orreducing one or more symptoms of retinal disease. In some variations,the first implant and the second implant may each comprise a drug fortreating or reducing one or more symptoms of AMD, and the drug may bethe same or a different drug. In another example, the first implant maycomprise a drug for treating or reducing one or more symptoms ofglaucoma and the second implant may comprise a drug for treating orreducing one or more symptoms of AMD.

The plurality of implants may be advanced to a desired position in theeye using the same, or different, approaches and/or delivery devices andsystems. For example, in some variations, methods may comprise advancinga first drug-eluting implant and a second drug-eluting implant throughconjunctiva and sclera of the eye of the subject and positioning aportion of the first implant and the second implant in the sclera and afirst end of the first implant and the second implant in the sulcus. Insome variations, methods may comprise advancing a first drug-elutingimplant and a second drug-eluting implant into the eye of the subject,and positioning a portion of the first implant in the posterior chamber(e.g., within the sulcus, within the sulcus and partially extending intothe remainder of the posterior chamber) and a portion of the secondimplant in the anterior chamber. In some variations, methods maycomprise advancing a first drug-eluting implant and a seconddrug-eluting implant into the eye, and positioning the entirety of thefirst implant in the intramural tissue (e.g., sclera, limbus, cornea)and a portion of the second implant in the anterior chamber. In somevariations, methods may comprise advancing a first drug-eluting implantand a second drug-eluting implant into the eye, and positioning theentirety of the first implant in the intramural tissue (e.g., sclera,limbus, cornea) and a portion of the second implant in the sulcus orposterior chamber. It should be understood that each implant positionedwithin the eye of the subject may treat the same or different conditionsof the eye.

Exemplary Embodiments

Embodiment I-1. An intraocular implant for treating a condition of theeye, the intraocular implant comprising:

an elongate implant body comprising a first end and a second end,wherein the elongate implant body is configured to be positioned atleast partially in the sclera such that the first end of the elongateimplant body is positioned in the posterior chamber or anterior chamber;

at least one anchoring element coupled to or formed from the elongateimplant body; and

a drug,

wherein the implant is configured to deliver the drug to the eye.

Embodiment I-2. The intraocular implant of embodiment I-1, wherein theelongate implant body comprises a filament, a sheet, a cylindricalcapsule, a coil, a rod, a screw, or a tubular body.

Embodiment I-3. The intraocular implant of embodiment I-1, wherein theelongate implant body comprises a tubular body and a plurality ofexpandable arms.

Embodiment I-4. The intraocular implant of embodiment I-1, wherein theelongate implant body comprises a tubular body, and wherein the at leastone anchoring element comprises a plurality of beads or barbs positionedalong a length of the tubular body.

Embodiment I-5. The intraocular implant of embodiment I-1 furthercomprising a housing coupled to the first end of the elongate implantbody and configured to be positioned in the sulcus or anterior chamber,wherein the housing comprises the drug.

Embodiment I-6. The intraocular implant of embodiment I-5, wherein anexternal surface of the housing is coated with the drug.

Embodiment I-7. The intraocular implant of embodiment I-5, wherein thehousing comprises a reservoir containing the drug.

Embodiment I-8. The intraocular implant of embodiment I-5, wherein thehousing is a coil.

Embodiment I-9. The intraocular implant of embodiment I-5, wherein thehousing is a cage.

Embodiment I-10. The intraocular implant of embodiment I-5, wherein thehousing comprises an erodible drug-eluting matrix.

Embodiment I-11. The intraocular implant of embodiment I-5, wherein thehousing is a canister comprising a shell and a hollow interior chamber.

Embodiment I-12. The intraocular implant of embodiment I-11, wherein thecanister comprises fenestrations through the shell to deliver the drugfrom the interior chamber to the eye.

Embodiment I-13. The intraocular implant of embodiment I-11, wherein thecanister comprises a first canister end and a second canister end.

Embodiment I-14. The intraocular implant of embodiment I-13, wherein thefirst canister end and second canister end are closed.

Embodiment I-15. The intraocular implant of embodiment I-13, wherein thefirst canister end comprises an opening and the second canister end isclosed.

Embodiment I-16. The intraocular implant of embodiment I-15, wherein theopening is sealed with a membrane permeable or semi-permeable to thedrug.

Embodiment I-17. The intraocular implant of embodiment I-13, wherein thefirst housing end comprises a first opening and second housing endcomprises a second opening.

Embodiment I-18. The intraocular implant of embodiment I-17, wherein atleast one of the first opening and second opening is sealed with amembrane permeable of semi-permeable to the drug.

Embodiment I-19. The intraocular implant of embodiment I-5, wherein theelongate implant body comprises a first longitudinal axis and thehousing comprises a second longitudinal axis, and wherein the housing iscoupled to the elongate implant body such that the first longitudinalaxis is parallel with the second longitudinal axis.

Embodiment I-20. The intraocular implant of embodiment I-5, wherein theelongate implant body comprises a first longitudinal axis and thehousing comprises a second longitudinal axis, and wherein the housing iscoupled to the elongate implant body such that the first longitudinalaxis is transverse with the second longitudinal axis

Embodiment I-21. The intraocular implant of embodiment I-5, wherein thehousing is refillable.

Embodiment I-22. The intraocular implant of embodiment I-5, wherein thehousing is erodible.

Embodiment I-23. The intraocular implant of embodiment I-1, wherein theelongate implant body comprises a drug-eluting matrix comprising thedrug.

Embodiment I-24. The intraocular implant of embodiment I-23, wherein thedrug-eluting matrix comprises a polymer.

Embodiment I-25. The intraocular implant of embodiment I-23, wherein thedrug-eluting matrix is erodible.

Embodiment I-26. The intraocular implant of embodiment I-23, wherein theelongate implant body comprises hollow interior chamber and a shell,wherein the elongate implant body further comprises fenestrationsthrough the shell to deliver the drug from the drug-eluting matrix inthe interior chamber to the eye.

Embodiment I-27. The intraocular implant of embodiment I-23, wherein thedrug-eluting matrix is in the form of a coating on an exterior surfaceof the elongate implant body.

Embodiment I-28. The intraocular implant of embodiment I-27, wherein thecoating is only on a first portion of the intraocular implant body.

Embodiment I-29. The intraocular implant of embodiment I-28, wherein thefirst portion of the implant is between the first end of the implantbody and the sclera.

Embodiment I-30. The intraocular implant of embodiment I-26, wherein thedrug-eluting matrix is in the hollow interior chamber of the elongateimplant body.

Embodiment I-31. The intraocular implant of embodiment I-1, wherein theelongate implant body is configured to be advanced into the eye throughsclera.

Embodiment I-32. The intraocular implant of embodiment I-1, where in thecondition of the eye is glaucoma, age-related macular degeneration(AMD), or retinal vascular disease.

Embodiment I-33. The intraocular implant of embodiment I-1, wherein theelongate implant body does not comprise a lumen for flow of aqueoushumor therethrough.

Embodiment I-34. The device of embodiment I-1, wherein the elongateimplant body comprises a polymer.

Embodiment I-35. The intraocular implant of embodiment I-34, wherein theelongate implant body comprises nylon, polypropylene,poly(styrene-block-isobutylene-block-styrene) (SIBS), or polyimide.

Embodiment I-36. The intraocular implant of embodiment I-34, wherein theelongate implant body comprises a filament.

Embodiment I-37. The intraocular implant of embodiment I-36, wherein thefilament comprises a plurality of braided fibers.

Embodiment I-38. The intraocular implant of embodiment I-36, wherein thefilament comprises a single fiber.

Embodiment I-39. The intraocular implant of embodiment I-36, wherein thefilament comprises polytetrafluoroethylene or polyester.

Embodiment I-40. The intraocular implant of embodiment I-1, wherein thesecond end of the elongate implant body is configured to be positionedentirely within the sclera.

Embodiment I-41. The intraocular implant of embodiment I-1, wherein thesecond end of the implant body is configured to be positioned outside ofthe sclera.

Embodiment I-42. The intraocular implant of embodiment I-41, wherein thesecond end of the elongate implant body is configured to be positionedin the subconjunctival space.

Embodiment I-43. The intraocular implant of embodiment I-1, wherein theat least one anchoring element comprises a first anchoring element and asecond anchoring element.

Embodiment I-44. The intraocular implant of embodiment I-44, wherein thefirst anchoring element is configured to be positioned within thesclera, and the second anchoring element is configured to be positionedbetween the first end of the implant and the sclera.

Embodiment I-45. The intraocular implant of embodiment I-44, wherein thefirst anchoring element is configured to be positioned within thesclera, and the second anchoring element is configured to be positionedbetween the second end of the implant and the sclera.

Embodiment I-46. The intraocular implant of embodiment I-43, wherein thefirst anchoring element is configured to reside between the second endof the elongate implant body and the sclera, and the second anchoringelement is configured to reside between the first end of the elongateimplant body and the sclera.

Embodiment I-47. The intraocular implant of embodiment I-1, wherein theat least one anchoring element comprises a knot, bead, barb, coil, orcrossbar.

Embodiment I-48. The intraocular implant of embodiment I-1, wherein thedrug is an antibody, a protein, or a biologic.

Embodiment I-49. The intraocular implant of embodiment I-48, wherein thedrug is ranibizumab, bevacizumab, or brolucizumab.

Embodiment I-50. The intraocular implant of embodiment I-1, wherein thedrug is travoprost, latanoprost, bimatoprost, aflibercept, riboflavin,or a corticosteroid.

Embodiment I-51. The intraocular implant of embodiment I-1, wherein thedrug is delivered to the eye over a period of time, wherein the periodof time is at least 1 month, at least 6 months, at least 1 year, atleast 2 years, or at least 3 years.

Embodiment I-52. The intraocular implant of embodiment I-1, wherein theelongate implant body comprises an erodible drug-eluting matrix, andwherein the first end of the elongate implant body has a first erosionrate and the second end of the elongate implant body has a second,different erosion rate.

Embodiment I-53. An intraocular implant for treating a condition of theeye, the intraocular implant comprising:

an elongate implant body configured to be positioned intramurally in oneor more of the sclera, the cornea, and the limbus; and

a drug-eluting matrix configured to release a drug to the eye,

wherein the drug-eluting matrix coats an exterior surface of theelongate implant body or is contained within an interior chamber of theelongate implant body.

Embodiment I-54. The intraocular implant of embodiment I-53, wherein theelongate implant body comprises a cylinder, a sheet, a filament, or acapsule comprising an interior chamber.

Embodiment I-55. An intraocular implant for treating a condition of theeye, the intraocular implant comprising:

a spherical or rod-shaped implant body configured to be positionedentirely in the sclera, wherein the spherical or rod-shaped implant bodycomprises an erodible drug-eluting matrix.

Embodiment I-56. A method of treating a condition in the eye of asubject, the method comprising:

advancing a drug-eluting implant through the conjunctiva and the scleraof the eye of the subject;

positioning a portion of the drug-eluting implant in the sclera and afirst end of the implant in the sulcus; and

delivering a drug from the drug-eluting implant to the sulcus of thesubject to reduce a symptom of the condition of the eye.

Embodiment I-57. The method of embodiment I-56, wherein the advancingthe drug-eluting implant through the conjunctiva and the scleracomprises advancing the drug-eluting implant in a delivery device.

Embodiment I-58. The method of embodiment I-57, wherein the deliverydevice comprises a needle, and the method further comprises puncturingthe sclera with the needle.

Embodiment I-59. The method of embodiment I-58, wherein the positioningstep comprises operating an actuator of the delivery device to releasethe implant from the delivery device.

Embodiment I-60. The method of embodiment I-58, wherein the deliverydevice further comprises a spring configured to retract the needle.

Embodiment I-61. The method of embodiment I-60, wherein the actuatorcomprises a button, a knob, or a slider.

Embodiment I-62. The method of embodiment I-56, wherein the implant isadvanced and/or positioned using loupes, a slit lamp, or a surgicalmicroscope.

Embodiment I-63. The method of embodiment I-56 further comprisingremoving the implant from the eye.

Embodiment I-64. The method of embodiment I-56 further comprisingadvancing a second drug-eluting implant through conjunctiva and scleraof the eye of the subject and positioning a portion of the secondimplant in the sclera and a first end of the second implant in thesulcus.

Embodiment I-65. The method of embodiment I-56, wherein the positioningstep further comprises fixing a position of the drug-eluting implantusing an anchoring element.

Embodiment I-66. The method of embodiment I-65, wherein the anchoringelement is positioned between the first end of the drug-eluting implantand the sclera.

Embodiment I-67. The method of embodiment I-65, wherein the anchoringelement is positioned in the subconjunctival space.

Embodiment I-68. The method of embodiment I-56, further comprisingfixing a position of the drug-eluting implant using a first anchoringelement and a second anchoring element.

Embodiment I-69. The method of embodiment I-67, wherein the firstanchoring element is positioned between the first end of thedrug-eluting implant and the sclera, and the second anchoring element ispositioned in the subconjunctival space.

Embodiment I-70. The method of embodiment I-68, wherein at least one ofthe first anchoring element and second anchoring element is anexpandable anchoring element.

Embodiment I-71. The method of embodiment I-68, wherein the firstanchoring element and the second anchoring element are knots; andwherein the first anchoring element is implanted within the sulcus andthe second anchoring element is implanted in the subconjunctival space.

Embodiment I-72. The method of embodiment I-56, wherein the drug-elutingimplant comprises a filament.

Embodiment I-73. The method of embodiment I-72, wherein the anchoringelement is a knot, and the knot is implanted within the sulcus.

Embodiment I-74. The method of embodiment I-57, further comprisingrefilling the drug-eluting implant.

Embodiment I-75. The method of embodiment I-56, further comprisinganchoring the drug-eluting implant within the sulcus, thereby resultingin minimal endothelial cell loss.

Embodiment I-76. The method of embodiment I-56, further comprisinganchoring the drug-eluting implant within the iridocorneal angle,thereby resulting in minimal endothelial cell loss.

Embodiment I-77. The method of embodiment I-56, wherein the drug-elutingimplant delivers a glaucoma drug.

Embodiment I-78. The method of embodiment I-56, wherein the drug-elutingimplant is a first drug-eluting implant, and the method furthercomprises positioning a second drug-eluting implant in the eye.

Embodiment I-79. The method of embodiment I-78, wherein the firstdrug-eluting implant comprises a drug with a first mechanism of action,and the second drug-eluting implant comprises a drug with a secondmechanism of action.

Embodiment I-80. The method of embodiment I-79, wherein the firstmechanism of action and the second mechanism of action are the same.

Embodiment I-81. The method of embodiment I-79, wherein the firstmechanism of action and the second mechanism of action are different.

Embodiment I-82. The method of embodiment I-79, wherein the firstmechanism of action is suppression of production of aqueous humor andthe second mechanism of action is increasing the drainage of aqueoushumor through the trabeculocanicular pathway or the uveoscleral pathway.

Embodiment I-83. The method of embodiment I-79, wherein both the firstand second mechanisms of action are suppression of aqueous humor.

Embodiment I-84. The method of embodiment I-79, wherein the firstmechanism of action is increasing the drainage of aqueous humor throughthe trabeculocanicular pathway and the second mechanism of action isincreasing the drainage of aqueous humor through the uveoscleralpathway.

Embodiment I-85. The method of embodiment I-79, wherein the first andsecond mechanisms of action are increasing the drainage of aqueous humorthrough the trabeculocanicular pathway.

Embodiment I-86. The method of embodiment I-79, wherein the first andsecond mechanism of action are increasing the drainage of aqueous humorthrough the uveoscleral pathway.

Embodiment I-87. The intraocular implant of embodiment I-1, wherein thefirst end of the elongate implant body is positioned in the sulcus.

Embodiment I-88. The intraocular implant of embodiment I-1, wherein theelongate implant body traverses the sulcus and extends less than about 2mm, less than about 1 mm, less than about 0.5 mm, or less than about0.25 mm from the sulcus into the posterior chamber.

Embodiment I-89. A method for treating a condition of an eye of asubject, the method comprising:

advancing a drug-eluting implant through a sclera of the eye;

positioning the drug-eluting implant fully intramurally in the eye withat least a portion of the drug-eluting implant in a limbus of the eye;and

delivering a drug from the drug-eluting implant to an anterior chamberof the eye to reduce a symptom of the condition of the eye.

Embodiment I-90. The method of embodiment I-89, wherein the drug-elutingimplant comprises an elongate implant body comprising a first end and asecond end.

Embodiment I-91. The method of embodiment I-90, wherein the first end ofthe elongate implant body is positioned in the limbus and the second endis positioned in the sclera.

Embodiment I-92. The method of embodiment I-90, wherein the first end ofthe elongate implant body is positioned in the cornea and the second endis positioned in the limbus.

Embodiment I-93. The method of embodiment I-90, wherein the elongateimplant body traverses the limbus, the first end of the elongate implantbody is positioned in a cornea of the eye, and the second end ispositioned in the sclera.

Embodiment I-94. The method of embodiment I-89, wherein advancing thedrug-eluting implant comprises advancing a portion of a delivery devicethrough a sclera of the eye, wherein the drug-eluting implant isdisposed within the delivery device.

Embodiment I-95. The method of embodiment I-94, wherein the drug-elutingimplant is disposed within a cannula of the delivery device.

Embodiment I-96. The method of embodiment I-95, wherein the drug-elutingimplant is disposed about 0.5 mm to about 1.0 mm from a distal tip ofthe cannula.

Embodiment I-97. The method of embodiment I-94, wherein the distal tipof the cannula enters the anterior chamber during positioning of thedrug-eluting implant.

Embodiment I-98. The method of embodiment I-94, wherein positioning thedrug-eluting implant comprises advancing a distal tip of the cannulaabout 0.5 mm to about 1.0 mm into the anterior chamber.

Embodiment I-99. The method of embodiment I-94, wherein positioning thedrug-eluting implant comprises retracting the cannula.

Embodiment I-100. The method of embodiment I-99, wherein the cannula isretracted via operation of an actuator of the delivery device.

Embodiment I-101. The method of embodiment I-99, wherein thedrug-eluting implant is released from the delivery device uponretraction of the cannula.

Embodiment I-102. The method of embodiment I-95, wherein thedrug-eluting implant is advanced and/or positioned using loupes, a slitlamp, or a surgical microscope.

Embodiment I-103. The method of embodiment I-102, wherein positioningfurther comprises visualizing the distal tip of the cannula in theanterior chamber of the eye using loupes, a slit lamp, or a surgicalmicroscope.

Embodiment I-104. The method of embodiment I-89, wherein the methodfurther comprises fixing a position of the drug-eluting implant to atissue of the eye using at least one anchoring element.

Embodiment I-105. The method of embodiment I-104, wherein the at leastone anchoring element is positioned in and fixed to the limbus.

Embodiment I-106. The method of embodiment I-104, wherein the at leastone anchoring element is positioned in and coupled to the sclera.

Embodiment I-107. The method of embodiment I-104, wherein the at leastone anchoring element comprises one or more of surface ridges, knobs,ribs, bulbs, and barbs.

Embodiment I-108. The method of embodiment I-89, wherein thedrug-eluting implant does not enter the anterior chamber.

Embodiment I-109. The method of embodiment I-89, wherein the drugdiffuses through the limbus or the sclera.

Embodiment I-110. The method of embodiment I-109, wherein the drugdiffuses to the anterior and posterior chamber of the eye.

Embodiment I-111. The method of embodiment I-109, wherein the drugdiffuses through the limbus to the anterior chamber and the cornea.

Embodiment I-112. The method of embodiment I-89, wherein the drug is aglaucoma drug.

Embodiment I-113. The method of embodiment I-112, wherein the drug isone or more of travoprost, bimatoprost, latanoprost, or unoprostone.

Embodiment I-114. The method of embodiment I-89, wherein thedrug-eluting implant is cylindrical, a rectangular prism, or a sheet.

Embodiment I-115. The method of embodiment I-114, wherein thedrug-eluting implant is from about 0.5 mm to about 2 mm in length.

Embodiment I-116. The method of embodiment I-115, wherein thedrug-eluting implant is from about 1 mm to about 1.5 mm in length.

Embodiment I-117. The method of embodiment I-114, wherein thedrug-eluting implant is from about 0.1 mm to about 0.5 mm wide.

Embodiment I-118. The method of embodiment I-117, wherein thedrug-eluting implant is from about 0.2 mm to about 0.3 mm wide.

Embodiment I-119. The method of embodiment I-89, wherein thedrug-eluting implant comprises poly(lactic-co-glycolic acid) (PLGA),poly(lactic acid) (PLA), or poly(glycolic acid) (PGA).

Embodiment I-120. A method of placing a drug-eluting implant, comprisinga drug, at least partially within a limbus of an eye of a subject, themethod comprising:

advancing a distal tip of a cannula of a delivery device through asclera and the limbus into an anterior chamber of the eye, wherein thedrug-eluting implant is disposed within the cannula; and

retracting the cannula and releasing the drug-eluting implant at leastpartially within the limbus.

Embodiment I-121. The method of embodiment I-120, wherein thedrug-eluting implant comprises an elongate implant body comprising afirst end and a second end.

Embodiment I-122. The method of embodiment I-120, wherein thedrug-eluting implant comprises a drug-eluting matrix comprising thedrug.

Embodiment I-123. The method of embodiment I-122, wherein thedrug-eluting matrix comprises a polymer.

Embodiment I-124. The method of embodiment I-120, wherein thedrug-eluting implant is erodible.

Embodiment I-125. The method of embodiment I-120, wherein advancing thedistal tip of the cannula comprises entering the sclera posterior to thelimbus.

Embodiment I-126. The method of embodiment I-125, wherein the distal tipof the cannula enters the sclera about 2 mm to about 3 mm posterior tothe limbus.

Embodiment I-127. The method of embodiment I-120, wherein the distal tipof the cannula is advanced about 0.5 mm to about 1.0 mm into theanterior chamber.

Embodiment I-128. The method of embodiment I-120, wherein thedrug-eluting implant is disposed within the cannula about 0.5 mm toabout 1.0 mm proximal to the distal tip of the cannula.

Embodiment I-129. The method of embodiment I-120, wherein afterreleasing the drug-eluting implant from the delivery device, thedrug-eluting implant resides fully intramurally.

Embodiment I-130. The method of embodiment I-129, wherein afterreleasing the drug-eluting implant from the delivery device, thedrug-eluting implant is positioned fully within the limbus.

Embodiment I-131. The method of embodiment I-121, wherein afterreleasing the drug-eluting implant from the delivery device, the firstend of the elongate implant body is positioned in the limbus and thesecond end is positioned in the sclera.

Embodiment I-132. The method of embodiment I-121, wherein afterreleasing the drug-eluting implant from the delivery device, the firstend of the elongate implant body is positioned in the cornea and thesecond end is positioned in the limbus.

Embodiment I-133. The method of embodiment I-121, wherein afterreleasing the drug-eluting implant from the delivery device, theelongate implant body traverses the limbus, the first end of theelongate implant body is positioned in a cornea of the eye, and thesecond end is positioned in the sclera.

Embodiment I-134. The method of embodiment I-120, wherein the methodfurther comprises positioning the drug-eluting implant at leastpartially within the limbus prior to retracting the cannula.

Embodiment I-135. The method of embodiment I-134, wherein positioningthe drug-eluting implant comprises visualizing the distal tip of thecannula in the anterior chamber.

Embodiment I-136. The method of embodiment I-135, wherein the distal tipof the cannula is confirmed, via visualization, to be about 0.5 mm toabout 1.0 mm into the anterior chamber.

Embodiment I-137. The method of embodiment I-135, wherein the positionof the distal tip of the cannula is confirmed, via visualization throughan anterior portion of the, eye using loupes, a slit lamp, or a surgicalmicroscope.

Embodiment I-138. The method of embodiment I-120, wherein the cannula isretracted via operation of an actuator of the delivery device.

Embodiment I-139. The method of embodiment I-138, wherein thedrug-eluting implant is released from the delivery device uponretraction of the cannula.

Embodiment I-140. The method of embodiment I-138, wherein the actuatorcomprises one or more of a button, a knob, and a slider.

Embodiment I-141. The method of embodiment I-120, wherein the deliverydevice comprises a spring configured to retract the cannula.

Embodiment I-142. The method of embodiment I-120, wherein thedrug-eluting implant does not enter the anterior chamber.

Embodiment I-143. The method of embodiment I-120, wherein the drugdiffuses through the limbus or the sclera.

Embodiment I-144. The method of embodiment I-143, wherein the drugdiffuses to the anterior and posterior chamber of the eye.

Embodiment I-145. The method of embodiment I-143, wherein the drugdiffuses through the limbus to the anterior chamber and the cornea.

Embodiment I-146. The method of embodiment I-120, wherein the drug is aglaucoma drug.

Embodiment I-147. The method of embodiment I-120, wherein the drug isone or more of travoprost, bimatoprost, latanoprost, or unoprostone.

Embodiment I-148. The method of embodiment I-120, wherein thedrug-eluting implant is cylindrical, a rectangular prism, or a sheet.

Embodiment I-149. The method of embodiment I-148, wherein thedrug-eluting implant is from about 0.5 mm to about 2 mm in length.

Embodiment I-150. The method of embodiment I-149, wherein thedrug-eluting implant is from about 1 mm to about 1.5 mm in length.

Embodiment I-151. The method of embodiment I-148, wherein thedrug-eluting implant is from about 0.1 mm to about 0.5 mm wide.

Embodiment I-152. The method of embodiment I-151, wherein thedrug-eluting implant is from about 0.2 mm to about 0.3 mm wide.

Embodiment I-153. The method of embodiment I-120, wherein thedrug-eluting implant comprises poly(lactic-co-glycolic acid) (PLGA),poly(lactic acid) (PLA), or poly(glycolic acid) (PGA).

Embodiment I-154. The method of embodiment I-120, wherein thedrug-eluting implant resides partially in the subconjunctival space.

EXAMPLES Example 1 An Ab-Externo Method for Delivering an IntraocularImplant

A delivery device comprising a needle may be inserted into the scleraabout 2 to about 2.5 mm posterior to the limbus to a guarded/controlleddepth (about 0.5 to about 2 mm into eye). Via actuation, a pusher rodadvances the implant in the needle via across the sulcus, with theimplant tip ending in sulcus/posterior chamber. An anchoring elementopens or expands in sulcus, and the needle is withdrawn. In somevariations, the implant may comprise a thread-like end, which may bepositioned on the conjunctiva and exposed. The conjunctiva may then belifted (e.g., with forceps) to tent over or otherwise cover the exposedend of the implant, allowing the end to slip into the subconjunctivalspace. Alternatively, the device may be placed using a similartechnique, such that the tip of the implant resides in Berger's space orthe Canal of Petit. Any of the drug-eluting implants described hereinmay be used, such as, for example, a fully erodible implant.

Example 2 An Ab-Externo Method for Delivering an Intraocular Implant

A delivery device comprising a needle with two marks may be insertedinto the limbus and advanced into the sclera to create an about 3 mmtunnel. It is then withdrawn about 2 mm. An actuator (e.g., an actuationbutton, slider, etc.) deploys the implant contained within the needleinto sclera/limbal zone. In some embodiments, the final implant lengthmay be about 1 mm, about 2 mm, about 3 mm, about 4 mm, about 5 mm, orabout 6 mm.

Example 3 An Ab-Externo Method for Delivering an Intraocular Implant

A delivery device comprising a side-open needle (e.g., such deliverydevice (1500) comprising needle 1502 depicted in FIG. 15 ) may beinserted about 2.5 mm posterior to the limbus to a target depth (about1.5 mm). Under direct visualization, the implant may be advanced throughthe needle via a push rod until the first end of the implant is insidethe eye and the push rod is fully advanced. The needle may then bewithdrawn, leaving the implant within the eye. In some variations, theimplant may have a thread-like end that may now be on the conjunctivaand exposed. The conjunctiva may then be lifted (e.g., with forceps) totent over or otherwise cover the implant, allowing the end of theimplant to slip into the subconjunctival space. Any of the drug-elutingimplants described herein may be used, such as, for example, a fullyerodible implant.

Example 4 An Ab-Interno Method for Delivering an Intraocular Implant

In another exemplary embodiment, a delivery device comprising a needlemay be inserted through the limbus, through the pupil, behind the iris,into the sulcus, and through the sclera, stopping in the subconjunctivalspace. The implant may then be advanced with a push rod, via an actuatorof the delivery device, through the needle until a portion of theimplant is visible through sclera. At this point, the extra-scleralportion of implant is either under or on the conjunctiva. The needle maybe withdrawn, and the second end of the implant body, which may compriseone or more anchoring features preventing it from being pulled back intoeye, may be positioned outside of the sclera. In some variations, theimplant may have a thread-like end that may now be on the conjunctivaand exposed. The conjunctiva may then be lifted, e.g., with forceps, totent over or otherwise cover the implant, allowing the end of theimplant to slip into the subconjunctival space. Any of the drug-elutingimplants described herein may be used, such as, for example, a fullyerodible implant.

Example 5 An Ab-Externo Method for Delivering an Intraocular Implant

In another exemplary embodiment, a tunnel or pocket is created in thewall of the eye that is about 50% the depth of the tissue (e.g., cornea,sclera, and/or limbus) using an instrument such as a corneal separator(for the creation of an intramural channel or tunnel in the cornea,limbus, or sclera) or a femtosecond laser. Next a delivery device isused to deploy the implant into this preformed space.

Example 6 An Ab-Interno Method for Delivering an Intraocular Implant

In another exemplary embodiment, a delivery device comprising a needlemay be inserted through the cornea, across the anterior chamber towardsthe anterior chamber angle. A needle is used to enter the suprachoroidalspace where the drug-eluting implant is placed completely in thesuprachoroidal space. Alternatively, the drug-eluting implant may bepartially placed within the suprachoroidal space, with a portion of thedrug-eluting implant residing within the anterior chamber. Any of thedrug-eluting implants described herein may be used, such as, forexample, a fully erodible implant.

Example 7 An Exemplary Erodible Implant to Lower Elevated IntraocularPressure

In one exemplary embodiment, an intraocular implant configured to beimplanted fully within the sclera comprises an implant body comprising acore of one or more erodible drug-eluting matrices of one or more drugsfor treating glaucoma. The implant body may be comprised of an erodiblepolymer configured to release the one or more drugs into the scleraltissue, where it may diffuse further into an internal chamber of the eye(e.g., anterior chamber). The rate of elution of the one or more drugsmay be constant or may change over time (e.g., due to the erosion of theerodible implant body). The implant may be configured such that the oneor more drugs elute faster from the drug-eluting matrices than theimplant body erodes.

Example 8 An Ab-Externo Method of Positioning and Delivering anIntraocular Implant Residing Intramurally in the Eye

In one exemplary embodiment, an intraocular implant is configured toreside intramurally in the eye with at least a portion of the implant ina limbus of the eye. The implant is delivered via a delivery device,where it is disposed within a cannula. The implant is disposed about 0.5mm to about 1.0 mm from the distal tip of the cannula. The cannulacontaining the implant is advanced through the sclera posterior to thelimbus of an eye. The cannula is then further advanced into the anteriorchamber to a depth corresponding to the offset of the implant from thedistal tip of the cannula (e.g., about 0.5 mm to about 10.0 mm) in orderto position the implant at least partially in the limbus without theimplant entering the anterior chamber. The implant is advanced orpositioned using loupes, a slit lamp, or a surgical microscope. Once thedistal tip of the cannula is visualized within the anterior chamber andconfirmed to be at the appropriate depth, the cannula is retracted viaat least one actuator of the delivery device, releasing the implantintramurally upon retraction of the cannula. The implant may have one ormore anchoring elements, including anchoring elements that deployintramurally once the cannula of the delivery device is retracted.

Example 9 Investigation of Bimatoprost-PLGA Drug-Eluting Implants inPigs

Poly(lactic-co-glycolic acid) (PLGA) implants comprising bimatoprostwere implanted into the eyes of 3 month old Yucatan pigs (6 pigs total).Prior to delivering the implant to either the sclera (fullyintrascleral; “intrascleral arm”) or partially in the limbus (one endresiding in the limbus, one end residing in the sclera; “limbal arm”),the pigs were placed under general anesthesia, and a lid speculum wasinserted. Intraocular pressure was checked, and corneal thickness waschecked in 4 quadrants, and centrally, using ultrasonic cornealpachymetry. The lid speculum was then removed.

In each of the 6 pigs, the right eye received one implant, and the lefteye received 2 implants. In order to accomplish this, betadine dropswere placed onto the left eyes of each pig and an eyelid speculum isinserted. A surgical operating microscope was positioned to visualizethe implantation. Each eye was infraducted with a traction suture. Asmall conjunctival peritomy was created, and the sclera was marked withgentian violet-tipped calipers 2 mm posterior to the limbus. 10-0 nylonmarking sutures were then placed 3-4 mm posterior to the limbus. A 27 Gneedle on a TB syringe was used to preform a tunnel for implantationtoward the anterior chamber (group 1) or across the sclera (group 2).The implant was then deployed into the preformed tunnel, and thetraction suture was released. Polymyxin-trimethoprim andtobramycin-dexamethasone drops were then placed in each eye, and thespeculum was removed. The procedure was then repeated with two implantsin each pig's right eye.

At week 2, the pigs were examined for redness, inflammation, eyerubbing, miosis, and squinting.

At month 1, the pigs were examined, and one pig from each group waseuthanized and the eyes were removed and placed in formalin forpathology. Aqueous samples from each of the 6 pigs were collected andanalyzed for the presence of bimatoprost and Bimatoprost Acid (ametabolite of bimatoprost). At weeks 3, 10, and 20, the remaining pigsin each group were examined for redness, inflammation, eye rubbing,miosis, and squinting, as above.

At month 3, the remaining pigs were examined and aqueous samplescollected (as above), and one of the remaining pigs from each group waseuthanized (as above) for pathology.

The histopathology of the eyes is evaluated, as is the concentration ofbimatoprost, and metabolites thereof, in the anterior chambers. Theconcentrations of bimatoprost and the bimatoprost acid metabolite in theanterior chamber of each pig's eyes are shown in FIGS. 24A-24D, at thetime points described above. FIG. 24A and FIG. 24B show theconcentrations of bimatoprost and the bimatoprost acid metabolite,respectively, for the three pigs (A1, A2, and A6) implanted with theintrascleral implant. FIG. 24C and FIG. 24D show the concentrations ofbimatoprost and the bimatoprost acid metabolite, respectively, for thethree pigs (A3, A4, and A5) implanted with the limbal implant. Asdemonstrated in these data sets, bimatoprost was detectable in theaqueous humor of both intrascleral and limbal arms. Additionallybimatoprost had both higher and more sustained aqueous levels in thelimbal arm compared to the intrascleral arm. Similarly, Bimatoprost Acidwas detectable in both animal arms and was also detected at a higherconcentration in the limbal arm compared to the intrascleral arm.

At month 6, the remaining pig from each group is examined and aqueoussamples are collected (as above), and each of the remaining pigs iseuthanized (as above) for pathology. At this point, the histopathologyof the eyes is evaluated, as is the concentration of bimatoprost, andmetabolites thereof, in the anterior chambers.

The foregoing description, for purposes of explanation, used specificnomenclature to provide a thorough understanding of the invention.However, it will be apparent to one skilled in the art that specificdetails are not required in order to practice the invention. Thus, theforegoing descriptions of specific embodiments of the invention arepresented for purposes of illustration and description. They are notintended to be exhaustive or to limit the invention to the precise formsdisclosed; obviously, many modifications and variations are possible inview of the above teachings. The embodiments were chosen and describedin order to explain the principles of the invention and its practicalapplications, they thereby enable others skilled in the art to utilizethe invention and various embodiments with various modifications as aresuited to the particular use contemplated. It is intended that thefollowing claims and their equivalents define the scope of theinvention.

1-119. (canceled)
 120. A method of placing a drug-eluting implant,comprising a drug, at least partially within a limbus of an eye of asubject, the method comprising: advancing a distal tip of a cannula of adelivery device through a sclera and the limbus into an anterior chamberof the eye, wherein the drug-eluting implant is disposed within thecannula; and retracting the cannula and releasing the drug-elutingimplant at least partially within the limbus.
 121. (canceled)
 122. Themethod of claim 120, wherein the drug-eluting implant comprises adrug-eluting matrix comprising the drug.
 123. The method of claim 122,wherein the drug-eluting matrix comprises a polymer.
 124. The method ofclaim 120, wherein the drug-eluting implant is erodible.
 125. The methodof claim 120, wherein advancing the distal tip of the cannula comprisesentering the sclera posterior to the limbus.
 126. The method of claim125, wherein the distal tip of the cannula enters the sclera about 2 mmto about 3 mm posterior to the limbus.
 127. The method of claim 120,wherein the distal tip of the cannula is advanced about 0.5 mm to about1.0 mm into the anterior chamber.
 128. The method of claim 120, whereinthe drug-eluting implant is disposed within the cannula about 0.5 mm toabout 1.0 mm proximal to the distal tip of the cannula.
 129. The methodof claim 120, wherein after releasing the drug-eluting implant from thedelivery device, the drug-eluting implant resides fully intramurally.130. (canceled)
 131. The method of claim 121, wherein after releasingthe drug-eluting implant from the delivery device, the first end of theelongate implant body is positioned in the limbus and the second end ispositioned in the sclera.
 132. The method of claim 121, wherein afterreleasing the drug-eluting implant from the delivery device, the firstend of the elongate implant body is positioned in the cornea and thesecond end is positioned in the limbus.
 133. The method of claim 121,wherein after releasing the drug-eluting implant from the deliverydevice, the elongate implant body traverses the limbus, the first end ofthe elongate implant body is positioned in a cornea of the eye, and thesecond end is positioned in the sclera.
 134. The method of claim 120,wherein the method further comprises positioning the drug-elutingimplant at least partially within the limbus prior to retracting thecannula.
 135. The method of claim 134, wherein positioning thedrug-eluting implant comprises visualizing the distal tip of the cannulain the anterior chamber.
 136. The method of claim 135, wherein thedistal tip of the cannula is confirmed, via visualization, to be about0.5 mm to about 1.0 mm into the anterior chamber.
 137. (canceled) 138.The method of claim 120, wherein the cannula is retracted via operationof an actuator of the delivery device.
 139. The method of claim 138,wherein the drug-eluting implant is released from the delivery deviceupon retraction of the cannula.
 140. (canceled)
 141. The method of claim120, wherein the delivery device comprises a spring configured toretract the cannula.
 142. The method of claim 120, wherein thedrug-eluting implant does not enter the anterior chamber.
 143. Themethod of claim 120, wherein the drug diffuses through the limbus or thesclera.
 144. The method of claim 143, wherein the drug diffuses to theanterior and posterior chamber of the eye.
 145. The method of claim 143,wherein the drug diffuses through the limbus to the anterior chamber andthe cornea.
 146. The method of claim 120, wherein the drug is a glaucomadrug.
 147. The method of claim 120, wherein the drug is one or more oftravoprost, bimatoprost, latanoprost, or unoprostone.
 148. The method ofclaim 120, wherein the drug-eluting implant is cylindrical, arectangular prism, or a sheet.
 149. The method of claim 148, wherein thedrug-eluting implant is from about 0.5 mm to about 2 mm in length.150-152. (canceled)
 153. The method of claim 120, wherein thedrug-eluting implant comprises poly(lactic-co-glycolic acid) (PLGA),poly(lactic acid) (PLA), or poly(glycolic acid) (PGA).
 154. The methodof claim 120, wherein the drug-eluting implant resides partially in thesubconjunctival space.